Penyakit Prion(1)

8/11/2019 Penyakit Prion(1)

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Penyakit prion

Jurnal 1Hum Mol Genet. 2012 April 15; 21(8): 1897–1906.Publi!e" online 2011 #e$ember %0. "oi: 10.109%&!m'&""r607PM#: PM%%1%791

Genome-wide association study in

multiple human prion diseases suggests

genetic risk factors additional to PRNP

*imon Me+",1 -+me p!ill,1 -o!n /e$ ,1 M+r Poulter ,1 r+$ +mpbell,1 -ei$+3o4e,1 G+r A"+mon,1 Hol'er Hummeri$!,1 orm+n lopp,2 n+M+ri+ $ert,2 Hri$! i$!m+nn,2 #!o+<+n A<+<i,% =in$ent Pl+'nol,% +n"+'i H. P+o,> -erome

!it?iel",1,5 Mi$!+el P. Alper,1,>,5 -o!n !itt+er ,6 #+@i" -. /+l"in',% n'+ err ,7 H+nret<$!m+r ,8 +n" -o!n ollin'e1,B

Aut!or in?orm+tion C Arti$le note C opri'!t +n" 3i$ene in?orm+tion C!i +rti$le !+ been $ite" b ot!er +rti$le in PM.Go to:

Abstract

Prion "ie+e +re ?+t+l neuro"e'ener+ti@e "ie+e o? !um+n +n" +nim+l $+ue" b t!emi?ol"in' +n" +''re'+tion o? prion protein (PrP). M+mm+li+n prion "ie+e +re un"ertron' 'eneti$ $ontrol but ?e4 ri ?+$tor +re no4n +i"e ?rom t!e PrP 'ene lo$u( PRNP ). o 'enome4i"e +o$i+tion tu" (GA*) !+ been "one +i"e ?rom + m+ll+mple o? @+ri+nt reut<?el"t–-+ob "ie+e (-#). e $on"u$te" GA* o? por+"i$-# (-#), @+ri+nt -# (@-#), i+tro'eni$ -#, in!erite" prion "ie+e, uru +n"reit+n$e to uru "epite +tten"+n$e +t mortu+r ?e+t. A?ter Du+lit $ontrol, 4e+n+le" 2000 +mple +n" 6015 $ontrol in"i@i"u+l (pro@i"e" b t!e ell$ome rut+e ontrol onortium +n" EA'en) ?or >910%2511862 *P in t!e urope+ntu". Ao$i+tion tu"ie 4ere "one in e+$! 'eo'r+p!i$+l +n" +etiolo'i$+l 'roup?ollo4e" b e@er+l $ombine" +n+le. !e PRNP lo$u 4+ !i'!l +o$i+te" 4it! riin +ll 'eo'r+p!i$+l +n" +etiolo'i$+l 'roup. !i +o$i+tion 4+ "ri@en b t!e no4n$o"in' @+ri+tion +t r1799990 ( PRNP $o"on 129). o non PRNP lo$i +$!ie@e" 'enome4i"e i'ni?i$+n$e in t!e met++n+li o? +ll !um+n prion "ie+e. *P +t t!e ZBTB38 – RASA2 lo$u 4ere +o$i+te" 4it! -# in t!e (r295%01, P F %.1% 108; E, 0.70) but t!ee *P !o4e" no repli$+tion e@i"en$e o? +o$i+tion in Germ+n -# or inP+pu+ e4 Guine+b+e" tet. A *P in t!e CHN2 'ene 4+ +o$i+te" 4it! @-# I P F1.5 107; o"" r+tio (E), 2.%6J, but not in -# ( P F 0.0>9; E, 1.2>), in Germ+n-# or in PG 'roup. n t!e o@er+ll met++n+li o? -#, 1> *P 4ere +o$i+te"( P K 105; t4o +t PRNP , t!ree +t ZBTB38 – RASA2, nine +t nine ot!er in"epen"ent non PRNP lo$i), more t!+n 4oul" be eLpe$te" b $!+n$e. one o? t!e lo$i re$entl i"enti?ie"+ 'enome4i"e i'ni?i$+nt in tu"ie o? ot!er neuro"e'ener+ti@e "ie+e !o4e" +n

http://dx.doi.org/10.1093%2Fhmg%2Fddr607

http://www.ncbi.nlm.nih.gov/pubmed/?term=Mead%20S%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Uphill%20J%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Beck%20J%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Poulter%20M%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Campbell%20T%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Lowe%20J%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Adamson%20G%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Hummerich%20H%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Klopp%20N%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=R%26%23x000fc%3Bckert%20IM%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Wichmann%20HE%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Azazi%20D%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Plagnol%20V%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Pako%20WH%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Whitfield%20J%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Alpers%20MP%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Whittaker%20J%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Balding%20DJ%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Zerr%20I%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Kretzschmar%20H%5Bauth%5D




http://www.ncbi.nlm.nih.gov/pubmed/?term=Collinge%20J%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313791/




http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313791/citedby/



http://www.ncbi.nlm.nih.gov/pubmed/?term=Mead%20S%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Beck%20J%5Bauth%5D







http://www.ncbi.nlm.nih.gov/pubmed/?term=Klopp%20N%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=R%26%23x000fc%3Bckert%20IM%5Bauth%5D




http://www.ncbi.nlm.nih.gov/pubmed/?term=Plagnol%20V%5Bauth%5D




http://www.ncbi.nlm.nih.gov/pubmed/?term=Alpers%20MP%5Bauth%5D



http://www.ncbi.nlm.nih.gov/pubmed/?term=Zerr%20I%5Bauth%5D



http://www.ncbi.nlm.nih.gov/pubmed/?term=Collinge%20J%5Bauth%5D






http://dx.doi.org/10.1093%2Fhmg%2Fddr607





i+tro'eni$ reut<?el"t–-+ob "ie+e (i-#) ?rom t!e ; 680 -# ?rom Germ+n; +n"568 +mple ?rom P+pu+ e4 Guine+ (PG) in$lu"in' uru +n" el"erl ?em+le ur@i@oro? t!e uru epi"emi$. !e () or EA (Germ+n) pro@i"e" 6507 $ontrol(2%). Ao$i+tion +n+le $on?irm t!e "omin+n$e o? PRNP + + ri ?+$tor rel+ti@e to +llot!er 'ene. e +re +ble to pro@i"e e@i"en$e ?or e@er+l +""ition+l 'eneti$ ri ?+$tor

+lt!ou'! none o? t!ee +$!ie@e" 'enome4i"e i'ni?i$+n$e in met++n+le bet4eenre'ion or +etiolo'ie.

Go to:

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A?ter Du+lit $ontrol (O), 8015 +mple 4ere +n+le" (ee M+teri+l +n" met!o").Ao$i+tion +n+li 4+ ?irt "one in in"i@i"u+l +etiolo'i$+l 'roup +n" 'eo'r+p!i$+lre'ion; t!ee 4ere t!en $ombine" in met++n+le. !e pre"etermine" prim+r tu"4+ + met++n+li o? !um+n prion "ie+e (+lleli$ tet, $+e–$ontrol "ei'n, -#,

@-#, reit+n$e to uru) ?rom +ll 'eo'r+p!i$+l re'ion. Et!er $ombin+tion +n"in"i@i"u+l +etiolo'i$+l +n" 'eo'r+p!i$+l tet 4ere e$on"+r out$ome, ?or eL+mple, +ll-#, -# +n" @-# in , -# ( or Germ+n +lone), @-#, uru (+'e o? "e+t!),reit+n$e to uru, P# (+'e o? onet), +n" -# (+'e o? onet). A + l+r'e proportion o?t!e ore popul+tion 4ere +??e$te" b uru in$lu"in' t!oe 4it! +pp+rent 'eneti$reit+n$e +t PRNP , 4e !pot!ei<e" t!+t $+e–$ontrol tu" 4oul" not be t!e bettr+te' +n" inte+" uru +'e o? "e+t! 4+ ue" + + Du+ntit+ti@e tr+it. A'e o? "e+t! inuru i i'ni?i$+ntl ol"er in PRNP $o"on 129 !etero<'ou in"i@i"u+l $omp+re" 4it!!omo<'ou in"i@i"u+l (2>). A imil+r e??e$t i een ?or e@er+l P#, +n" in + imil+r4+, +'e 4+ ue" + + Du+ntit+ti@e tr+it (25 – 27).

n t!e o@er+ll met++n+li o? +lleli$ tet, t!e topr+ne" +o$i+tion 4+ t!e no4n+mino+$i" polmorp!im +t PRNP $o"on 129 r1799990 Io@er+ll P F 6.58 107, o""r+tio (E) F 0.77; in -# 'roup, P F 1.2> 108;+ble 1J; !o4e@er, t!ere 4+$oni"er+ble !etero'eneit bet4een t!e +n" Germ+n prob+bl be$+ue o? $+e+$ert+inment (, E F 0.8>; Germ+n, E F 0.60, !i'!l i'ni?i$+nt "i??eren$e !o4n4it! t!e ue o? + o$!r+n–M+ntel–H+en<el tet ?or + 2 2 2 t+ble +n" /relo4#+tet o? !omo'eneit implemente" uin' P3) (i'. 1). ot+bl, in e@er+l prion"ie+e, r1799990 $on?er reit+n$e in t!e !etero<'ou t+te; t!ere?ore, +n +lleli$mo"el "oe not optim+ll $+pture t!e i'n+l +t t!i lo$u. !ree ot!er *P 4ere+o$i+te" 4it! t!e PRNP lo$u in -# +t P K 105: r2756271, r6107516 +n"r6116>77. +$! o? t!ee *P !+" lin+'e "ieDuilibrium (3#) 4it! r1799990 r 2Q 0.%,

+n" $on"ition+l or tr+ti?ie" +n+le u''ete" t!+t t!e entire +o$i+tion i'n+l 4+$on?erre" b r1799990. Alt!ou'! t!e prim+r +n+li ue" +n +lleli$ mo"el, + 'enotpi$mo"el !o4e" + mu$! tron'er i'n+l, + eLpe$te"; ?or eL+mple, +t r1799990 in -#, P 'enoF %.85 1025 +n" in Germ+n -#, P 'enoF 2.51 10%1, 4it! + "e?i$it o?!etero<'ou 'enotpe $onitent 4it! t!e no4n prote$ti@e e??e$t +t t!i lo$u (6).ontr+r to ot!er tu"ie, t!i GA* pro@i"e" no e@i"en$e o? +""ition+l ri +t t!e lo$uin -# (1>,28 – %0). *P r2756271 4+ 'enotpe" in t!e $urrent tu" +n" !o4e" @er!i'! 3# 4it! *P r102927% (r 2F 0.9>) 'enotpe" in pre@iou tu"ie in -# $+e

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313791/#DDR607C23





http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313791/table/DDR607TB1/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313791/figure/DDR607F1/



















(1>,28 – %0). on"ition+l +n+li b+e" on r2756271–r1799990 !+plotpe ?reDuen$iein $+e +n" $ontrol !o4e" no e@i"en$e ?or +""ition+l ri $on?erre" (r2756271– r1799990 !+plotpe E, AA F 1.>19, GA F 1.%8>, P F 0.65, implemente" 4it! P3).

+ble 1.op r+ne" +o$i+tion or"ere" b P @+lue b+e" on met++n+li o? @-#, -# +n"uru reit+n$e

i'ure 1.M+n!+tt+n plot !o4in' P @+lue ?rom +lleli$ (1 ".?.) +n" 'enotpi$ (2 ".?.) $!iDu+re"tet ?or ?i@e GA* tu"ie in@ol@in' (A) @-# @eru $ontrol (2), (() -# @eru $ontrol, ($) Germ+n -# @eru Germ+n $ontrol (EA), (") uru)))

Ai"e ?rom t!e PRNP lo$u, t!ere 4ere no 'enome4i"e i'ni?i$+nt +o$i+tion in t!e pre"etermine" met++n+li o? +ll !um+n prion "ie+e; !o4e@er, ot!er lo$i "i" pro@i"ee@i"en$e o? +o$i+tion in in"i@i"u+l +etiolo'i$+l $+te'orie or re'ion. !e top non PRNP lo$u 4+ +t ZBTB38 – RASA2 on $!romoome % (i'. 2) 4it! r9857275 ( P F 1.5% 106, E F 0.7817), r1%095>5% +n" r678507% ( P K 105). n t!e , +ll -# +n+li,t!e topr+ne" +o$i+tion +i"e ?rom PRNP , 4+ +t t!e ZBTB38 – RASA2 lo$u, r295%01( P F %.1% 108, E F 0.70; -#: P F %.7% 106, E F 0.72; @-#: P F 0.001>, E F0.628>); !o4e@er, t!i *P !o4e" no e@i"en$e o? +o$i+tion in Germ+n -# or inPG. !ee *P !+@e p+ir4ie 3# (r 2 Q 0.%) o@er %00 b on $!romoome % (i'. 2).295%01 +lo !o4e" 4e+ e@i"en$e o? + mo"i?in' e??e$t on +'e o? onet o? -# (+

+ Du+ntit+ti@e tr+it) 4it! t!e ri +llele bein' +o$i+te" 4it! +n e+rlier +'e o? onet ( P F0.0>).




















i'ure 2.llutr+tion o? +o$i+tion i'n+l ?rom t!e top t4o +o$i+te" 'eneti$ lo$i in t!i tu"( +n" Germ+n -# met++n+li; PP lo$u, top; //%8 lo$u, bottom). 3o'10 P i !o4n ?rom +n +lleli$ tet uin' bot! 'enotpe" +n" impute" *P )))

Et!er lo$i ( P K 105

) in t!e prim+r tu" met++n+li +re !o4n in +ble 1. n tot+l, 1>*P 4ere +o$i+te", P K 105 (2 +t PRNP +n" 12 *P +t 10 in"epen"ent non PRNP lo$i). e eL+mine" 4!et!er 4e ?oun" +n eL$e o? P K 105 in t!ree 4+. irt, b permutin' t!e $+e–$ontrol t+tu o? +ll ub'roup $ontributin' to t!e met++n+li (eeM+teri+l +n" met!o"), 4e ?oun" Q1% *P on 8&500 permut+tion (RPoion ?itte" P F0.01>) +n" Q11 *P on 19&500 permut+tion (RPoion P F 0.0%8). *e$on", t!e binomi+l prob+bilit o? Q1% *P ( P K 105) (n F 511862 tet) 4+ P F 0.001 +n" Q11*P 4+ P F 0.007; 4e +lo +$$ounte" ?or 3# b etim+tin' t!e e??e$ti@e number o?in"epen"ent tet (ee M+teri+l +n" met!o"), Q9 in"epen"ent lo$i (n F %7>9>%) P F0.005 +n" Q10 in"epen"ent lo$i P F 0.002. in+ll, t!e Q@+lue 4+ 0.%% ?or +ll 1> *P, P K 105 (ee M+teri+l +n" met!o"). one o? t!ee lo$i !o4e" +n e@i"en$e o?

+o$i+tion in uru, uru reit+n$e, or P# ("+t+ not !o4n). Alt!ou'! e@er+l *P4ere not polmorp!i$ in t!e ore popul+tion, t!ere 4ere no +o$i+tion i'n+l ( P K 0.01)"ete$te" +t t!ee lo$i S50 b.

n t!e in"i@i"u+l "ie+e $+te'orie, t!ere 4+ onl one non PRNP ?in"in' +t +roun"le@el o? 'enome4i"e i'ni?i$+n$e in t!e CHN2 'ene in @-#, r1016726, P F 1.5 107 (E, 2.%6), +n" m+r'in+ll in -# P F 0.0>9 (E, 1.2>), but not Germ+n -#or in PG 'roup. Ao$i+tion pre@ioul "e$ribe" +t t!e RARB – THRB lo$u +n"uptre+m o? STMN2 4ere unurpriin'l imil+r but not tron'er t!+n t!oe +lre+" publi!e" + t!ere 4+ +n +lmot $omplete o@erl+p in @-# +mple 4it! t!e $urrenttu" (1>). All ot!er "ie+e $+te'orie !o4e" no *P, P K 106.

nlie @-#, -# i + !etero'eneou $on"ition $+ue" b multiple prion tr+in tpe(%1). e t!ere?ore ou'!t to eLplore e@i"en$e o? +o$i+tion in "e?ine" ub'roup o?-#. !e $o"on 129 polmorp!im (r1799990) i + po4er?ul "etermin+nt o? tr+inele$tion (%2); !o4e@er, 4e ?oun" no e@i"en$e o? +n inter+$tion bet4een t!ee 10 lo$i+n" r1799990. *tr+ti?i$+tion +t r1799990 "i" not tren't!en +n o? t!e top +o$i+tionor re@e+l +n ne4 lo$i ( P K 106). Prion tr+in +re no4n to "etermine e $lini$+l?e+ture u$! + +'e o? onet but no 'enome4i"e i'ni?i$+nt lo$i 4ere i"enti?ie" 4!entetin' onl -# preentin' prior to +'e 60.

no4n 'enome4i"e i'ni?i$+nt +o$i+tion in rel+te" neuro"e'ener+ti@e $on"ition!o4e" no $le+r$ut e@i"en$e o? +o$i+tion in + imil+r "ire$tion in prion "ie+e(i'. %). 2102808 +t STK39 !o4e" +n +o$i+tion 4it! tron'er e??e$t t!+n t!+t"e$ribe" ?or P+rinonN "ie+e in @-#, -# +n" Germ+n -# 4it! imil+r Ein +ll 'roup (i'. %, *upplement+r M+teri+l, +ble *1).









http://hmg.oxfordjournals.org/lookup/suppl/doi:10.1093/hmg/ddr607/-/DC1











i'ure %.*tren't! o? +o$i+tion +t lo$i no4n to be in@ol@e" in ot!er neuro"e'ener+ti@e "ie+e.#ot re?er to etim+te o? E ?rom t!e topr+ne" *P in publi!e" +o$i+tion tu"ieo? +ltern+ti@e neuro"e'ener+ti@e "ie+e (ee *upplement+r M+teri+l, +ble )))Go to:

"I&$#&&I!N

e report t!e ?irt GA* o? -# +n" uru +n" t!e ?irt tu" po4ere" to "ete$tmo"er+tel tron' ri lo$i in !um+n prion "ie+e (E Q 1.5). e $oni"ere" e@er+l"i??erent !pot!ee o? 'eneti$ ri, in$lu"in' 4!et!er e??e$t 4ere "ie+e ubtpe orre'ion pe$i?i$, +n" 4!et!er poible ri +llele mo"i? $lini$+l p!enotpe. n 2009, 4e publi!e" ?in"in' ?rom + GA* in @-#, u''etin' *P uptre+m o? t!e RARB +n"STMN2 lo$i 4ere $+n"i"+te ?or @-# +o$i+tion; !o4e@er, t!i tu" 4+ onl po4ere"to "ete$t @er tron' e??e$t "i$o@ere" in @-# (1>). nurpriin'l, in t!e $urrenttu", PRNP 'enotpe 4ere tron'l +o$i+te" 4it! ri in +ll "ie+e $+te'orie +n"re'ion. o ot!er lo$u !o4e" + imil+rl tron' or uni@er+l +o$i+tion. n t!e met++n+li, !o4e@er, 10 ot!er lo$i 4ere ?oun" to +ppro+$! t!e t+titi$+l t!re!ol" ?or

u''eti@e GA* i'ni?i$+n$e ( P K 105), beon" t!e number eLpe$te" b $!+n$e,$onitent 4it! e@er+l mo"et 'eneti$ e??e$t. urt!er 'eneti$ +n+le +re reDuire" to pro@i"e $on@in$in' e@i"en$e ?or +o$i+tion +t t!ee lo$i. e +lo "emontr+te t!+t it i?e+ible to $on"u$t GA* on ol" "e'r+"e" +n" +mpli?ie" #A in t!e uru +r$!i@e$olle$tion.

A 4e+lt! o? e@i"en$e pl+$e PrP $entr+ll in t!e p+t!o'enei o? +ll prion "ie+e. !e'eneti$ +o$i+tion +t PRNP 4+ @er tron' +n" preent +$ro re'ion, "ie+e ubtpe+n" $lini$+l p!enotpe +lbeit 4it! "i??erent 'eneti$ mo"el in +etiolo'i$+l ub'roup. oreL+mple, in @-#, +ll but one +mple 4+ !omo<'ou A (en$o"in' met!ionine) +tr1799990 ($o"on 129), 4!ere+ bot! !omo<'ou 'enotpe 4ere +t in$re+e" ri

rel+ti@e to !etero<'ou in +ll ot!er "ie+e 'roup.

*e@er+l tu"ie !+@e reporte" +""ition+l 4e+ +o$i+tion 4it! -# or @-# +t t!e PRNP lo$u beon" t!+t $on?erre" b r1799990 or ot!er miene polmorp!im(1>,28 – %0). n t!i tu", our $on"ition+l +n+le "i" not upport t!ee ?in"in' 4it! noe@i"en$e ?or +""ition+l ?+$tor; poible eLpl+n+tion in$lu"e "i??erent *P 'enotpe"(+lt!ou'! 4e !+@e !o4n t!e 'enotpe" *P 4+ +n eL$ellent urro'+te ?or + pre@ioulreporte" ri +llele), t!e ?+ilure o? imput+tion to +$$ur+tel 'enotpe ot!er *P, +n"




















'eneti$ ri ?+$tor t!+t 4oul" be "ilute" in + tu" un+ble to $orre$tl +$ert+in+etiolo'. in+ll, it i poible t!+t om+ti$ mut+tion or to$!+ti$ (proteinb+e") e@ent+re $entr+l to +etiolo' +n" 'eneti$ mo"i?ier pl+ onl + @er m+ll role in t!e"o4ntre+m ri o? $lini$+l "ie+e.

uture 4or !oul" prioriti<e ?urt!er GA* in "i??erent popul+tion +n" tu"ie "ei'ne"to +$ert+in r+rer *P 4it! poibl l+r'er ?un$tion+l e??e$t, +n+li o? $op number@+ri+tion, p+t!4+ +n+li +n" ?urt!er tu" o? t!e mo"i?i$+tion o? $lini$+l p!enotpe b'eneti$ polmorp!im.

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*AT%IA'& AN" *%T+!"&

+uman samples

!e $lini$+l +n" l+bor+tor tu"ie 4ere +ppro@e" b t!e lo$+l ree+r$! et!i$ $ommitteeo? ni@erit olle'e 3on"on ntitute o? eurolo' +n" +tion+l Hopit+l ?or eurolo' +n" eurour'er +n" b t!e Me"i$+l ee+r$! A"@ior ommittee o? t!eGo@ernment o? PG. ull p+rti$ip+tion o? t!e PG $ommunitie in@ol@e" 4+et+bli!e" +n" m+int+ine" t!rou'! "i$uion 4it! @ill+'e le+"er, $ommunitie,?+milie +n" in"i@i"u+l. A$$e to -# p+tient 'enotpe "+t+ i +@+il+ble t!rou'! t!europe+n GenomeP!enome Ar$!i@e +t t!e urope+n /ioin?orm+ti$ Ar$!i@e (+$$eionnumber GA*00000000097).

,ariant $reutfeldt.Jakob disease

Prob+ble or "e?inite @-# p+tient, "i+'noe" +$$or"in' to et+bli!e" $riteri+(!ttp:&&444.+"@iorbo"ie."o!.'[email protected]&+$"p&te'ui"+n$e&te'ui"+n$eT+nneLb.p"? ), 4erere$ruite" b t!e +tion+l Prion lini$ (P), 3on"on or t!e +tion+l -# ee+r$! +n"*ur@eill+n$e nit, "inbur'!, ?rom 1995 to 2010. Genomi$ #A 4+ uu+ll eLtr+$te"?rom perip!er+l bloo"; br+in tiue 4+ ue" + + our$e ?or ome p+tient. Ampli?ie"#A, uin' eit!er multiple "ipl+$ement +mpli?i$+tion (Geneer@i$e, +mbri"'e, ) or ?r+'ment+tionP met!o" (GenomepleL, *i'm+), 4+ ue" ?or + m+ll number (K10U)o? +mple. *+mple 4ere $!e$e" ?or "e'r+"+tion on 1U +'+roe 'el +n" tore" +t 50n'&Vl in ri#A bu??er. All p+tient 4ere t!ou'!t to !+@e +$Duire" t!e "ie+e in t!e. Me+n +'e o? "ie+e onet 4+ %0 e+r, 56U 4ere m+le.

&poradic $reutfeldt.Jakob disease

Prob+ble or "e?inite -# p+tient, +$$or"in' to HE $riteri+, 4ere re$ruite" b t!e P, 3on"on, t!e -#*, "inbur'!, or numerou ot!er re?errer in t!e . #A4+ our$e" +n" +mpli?ie" + ?or @-#. All p+tient 4ere o? or nort!ern urope+nori'in. Alt!ou'! t!e @+t m+orit o? p+tient 4ere o? 4!ite/riti! et!ni$it, +n" +ll p+tient o? no4n non4!ite et!ni$it 4ere eL$lu"e", t!i in?orm+tion 4+ b+e" on


http://www.advisorybodies.doh.gov.uk/acdp/tseguidance/tseguidance_annexb.pdf


http://www.advisorybodies.doh.gov.uk/acdp/tseguidance/tseguidance_annexb.pdf



n+me +n" 'eo'r+p! ?or ome +mple. #A prep+r+tion +n" tor+'e 4+ imil+r to@-#. n t!e 61U !+" p+t!olo'i$+ll $on?irme" -#, t!e rem+in"er !+" + "i+'noio? prob+ble -# +$$or"in' to t!e publi!e" HE $riteri+ 4it! + !i'! pe$i?i$it.Me"i+n +'e o? onet o? "ie+e 4+ 65 e+r (15–87); 272 p+rti$ip+nt 4ere ?em+le. nGerm+n, +ll $+e 4ere p+t!olo'i$+ll $on?irme", me"i+n +'e o? onet 4+ 66 (r+n'e

19–90); %06 p+rti$ip+nt 4ere ?em+le.

/uru0elderly women resistant to kuru

Prior to 1987, uru ur@eill+n$e 4+ $on"u$te" b m+n "i??erent in@eti'+tor(G+"ue, i'+, /+er, Alper, Horn+broo, Moir +n" ot!er) +n" ?rom 1987 to 1995olel b t!e uru *ur@eill+n$e e+m o? t!e PG ntitute o? Me"i$+l ee+r$!. rom1996 on4+r", uru ur@eill+n$e 4+ tren't!ene" +n" + ?iel" b+e +n" b+i$ l+bor+tor?or +mple pro$ein' +n" tor+'e 4+ et+bli!e" in t!e @ill+'e o? +i+ in t!e *out!ore. !e uru $olle$tion $omprie" oun' $!il"ren, +"ole$ent +n" +"ult ?rom +roun"t!e pe+ o? t!e epi"emi$ +n" el"erl re$ent uru $+e 4it! lon' in$ub+tion time.

l"erl eLpoe" 4omen 4ere "e?ine" + +'e" o@er 50 e+r in 2000 ?rom + urueLpoe"re'ion. !ee 4omen 4ere un+??e$te" +t t!e time o? +mplin' but 4ere t!ou'!t to !+@e been eLpoe" to uru prion in $!il"!oo". Alt!ou'! t!ee 4omen m+ not be trulWreit+ntX to uru prion t!e 4oul" !+@e in$ub+tion time in eL$e o? >0 e+r.A""ition+l $ontrol 4ere obt+ine" ?rom t!e oun' mo"ern "+ !e+lt! popul+tion t!+t!+ not been eLpoe" to uru but $+me ?rom @ill+'e in t!e eLpoe" re'ion b m+t$!in'e+$! el"erl 4om+n (Wreit+ntX) to +t le+t t4o $urrent rei"ent o? t!e +me @ill+'e +'e"K50 in 2000. !ee l+r'el $+me ?rom t!e *out! ore, but 4it! + i'ni?i$+nt number ?romt!e ort! ore +n" + m+ll number o? in"i@i"u+l ?rom Gimi, ei+'+n+ +n" Y+'+ri+lin'uiti$ 'roup. urt!er $ontrol 4ere obt+ine" ?rom oun' uneLpoe" people ?rom

+re+ o? PG 4!ere no uru !+ been re$or"e". !ere i"enti?ie" b eit!er 'ene+lo'i$+l"+t+ or mi$ro+tellite +n+li, ?irt "e'ree rel+ti@e 4ere eL$lu"e" ?rom t!ee 'roup.#A ?rom "e'r+"e" +r$!i@+l uru er+, obt+ine" ?rom t!e H $olle$tion, 4+ iol+te" b OAG OA+mp /loo" #A miniit ?ollo4e" b 4!ole 'enome +mpli?i$+tioneit!er t!rou'! uin' + Z29 proto$ol (Geneer@i$e) or GenomePleL omplete !oleGenome Ampli?i$+tion it (*i'm+).

uality control

ot+ll, 8>0 EA $ontrol 4ere 'enotpe" on 550 llumin+ +rr+ +n" 56672 $ontrol on t!e llumin+ 1.2M utom #uo +rr+; $+e 4ere 'enotpe" on t!e

llumin+ 660. +e in$lu"e" 680 Germ+n -# +mple, 579 -#, 1%% @-#(+n" 5 non @-#), 165 uru +mple, 125 uru reit+nt 4omen +n" 286'eo'r+p!i$+ll m+t$!e" $ontrol in"i@i"u+l. !ere 4+ no "i$rep+n$ bet4een reporte"+n" 'eneti$ 'en"er in t!e $+e.

Prior to +n+li, +mple 4ere remo@e" ?rom t!e 2 "+t+ et b t!eir pre$ribe"$riteri+. !e 2 $!oe $riteri+ to be imil+r to t!oe o?ten +pplie" + t+n"+r" inGA tu"ie. n"i@i"u+l 4ere eL$lu"e" i? t!e "ipl+e" + "iproportion+te number o?



!etero<'ou or miin' $+ll. el+te" in"i@i"u+l 4ere eL$lu"e" +$$or"in' to i"entit b"e$ent (/#). n"i@i"u+l 4ere eL$lu"e" on t!e b+i o? +n$etr i? t!e "i??ere" ?romt!e m+orit o? t!e $olle$tion +$$or"in' to + prin$iple $omponent +n+li o? H+pM+pin"i@i"u+l. Gen"er "i$rep+n$ bet4een t!e upplier +n" t!e in?erre" 'en"er +lo le" to+mple remo@+l. n"i@i"u+l 4ere eL$lu"e" i? t!e me+n o? t!eir A +n" / +llele intenitie

4ere outlier 4!en $omp+re" 4it! t!e +mple +t l+r'e. n tot+l, >67 2 in"i@i"u+l4ere remo@e" le+@in' 5200 +mple $omprie" o? 26%0 m+le +n" 2570 ?em+le.

e ue" + 98U +mple 'enotpin' $+ll t!re!ol" ?or t!e m+in +o$i+tion tet; !o4e@er,+n 80U +mple $+ll r+te 4+ +pplie" to t!e uru +mple. !i +llo4e" u to ret+in 90Uo? t!i m+ll +n" uniDue $+e erie. Eber@+tion o? $on$or"+n$e bet4een no4n"upli$+te p+ir (n F 8) "emontr+te" t!+t t!e o@er+ll 'enotpe error 4+ K0.00085 4it! ++mple $+ll r+te +bo@e 80U. An+le uin' uru +mple 4ere retri$te" to t!i+etiolo'i$+l 'roup +lone uin' +'e +t "e+t! + + Du+ntit+ti@e tr+it to minimi<e t!e poibilit o? intro"u$in' bi+ b $omp+rin' $o!ort 4it! "i??erent O. rpti$"upli$+te 4ere i"enti?ie" uin' t!e t+titi$+l 'eneti$ me+ure o? rel+te"ne, pi!+t. !e

t!re!ol" ?or eL$luion 4+ pi!+t Q 0.8. A ubet o? 200 *P $ommon to +ll t!ree+rr+ +n" ele$te" ?or t!e !i'!et minor +llele ?reDuen$ (MA) 4ere ue" to "eri@e pi!+t etim+te. Enl $rpti$ "upli$+te 4ere "i$o@ere" +n" no !i'!l rel+te" in"i@i"u+l.*tep 4ere t+en to i"enti? et!ni$ outlier 4it!in t!e +mple et. A ?or t!e pi!+tetim+te, t!e +me 200 *P 4ere ue" to "eri@e i"entit b t+te etim+te 4!i$!4ere plotte" on t!e ?irt t4o +Le o? + multi"imenion+l $+lin' plot. *+mple outi"et!e m+in $luter 4ere eL$lu"e". !ole 'enome +mpli?ie" +mple "i" not +ppe+r +outlier +n" o 4ere ret+ine". A?ter +mple O, 815 EA, 6%> Germ+n -#, 522-# +n" 125 @-# +mple 4ere ret+ine" ?or +n+li. i@e pre@ioul no4nnon @-# +mple +ppe+re" outi"e t!e m+in $luter.

OO plot +n" 'enomi$ $ontrol in"i$+te" mo"et or no in?l+tion o? t!e +o$i+tion tett+titi$ in +ll eL$ept t!e Germ+n tu" (l+mb"+, @-# F 1; -# F 1.02;Germ+n -# F 1.12; ore F 0.99) (ee *upplement+r M+teri+l, i'ure *1). e "i" not?in" e@i"en$e o? te$!ni$+l +rte?+$t rel+te" to t!e ue o? "i??erent 'enotpin' +rr+(t!rou'! eL+min+tion o? OO plot o? *P 4it! "i??erent +llele ?reDuen$ie, "i??erenti+lmiin'ne +n" H+r"–einber' eDuilibrium, or +o$i+tion 4it! 'enotpin' b+t$!e).e $on$lu"e" t!+t popul+tion tr+ti?i$+tion 4+ t!e mot liel eLpl+n+tion. orre$tionuin' prin$iple $omponent (i'entr+t) re"u$e" l+mb"+ in t!e Germ+n tu" ?rom 1.11to 1.0%7. or met++n+li, Germ+n P @+lue +n" E t+n"+r" error 4ere $orre$te" bt!e 'enomi$ $ontrol (G) met!o" (ee *upplement+r M+teri+l, i'ure *1) (%6). Allele?reDuen$ie 4ere m+re"l "i??erent in t!e PG popul+tion + eLpe$te", +n" o +"i??erent et o? 175 *P 4+ +pplie" to t!e PG +mple. o PG +mple 4ereremo@e" + et!ni$ outlier.

*P O 4+ +pplie" to t!e $ontrol "+t+ to'et!er 4it! t!e $+e. *P 4it! + miin'neQ 1U; MA K 1U, or !o4in' "ep+rture ?rom H+r"–einber' eDuilibrium in $ontrol( P K 1 10%) 4ere eL$lu"e". *P to be eL$lu"e" @+rie" "epen"in' upon t!e$omp+rion bein' m+"e. A eLpe$te" t!e m+orit o? *P eL$lu"e" in t!e PG$omp+rion 4ere "ue to lo4 minor +llele ?reDuen$ie in t!e PG popul+tion. *P









r1799990 4+ miin' ?rom t!e 550 EA $ontrol et +n" t!e 660 $+e but 4+ preent on t!e 1.2M utom #uo 2 $!ip. *P r1799990 4+ 'enotpe" ?or t!emiin' +mple uin' +lleli$ "i$rimin+tion P probe +n" t!e "+t+ +""e" to t!e "+t+et. !i *P p+e" +ll ot!er O me+ure +n" o 4+ ret+ine" in t!e tu" to +llo4tu" o? t!e PRNP +o$i+tion +n" tr+ti?i$+tion.

!e 1000 Genome Pilot (-une 2010) [ H+pM+p% (ebru+r 2009) p+nel 4+ ue"to impute *P 2.5 Mb uptre+m +n" "o4ntre+m o? our lo$i o? interet (mentione"+bo@e). *P 4ere tr+n" +li'ne" +n" p!+e", prior to imput+tion uin' t!e pro'r+mmputeT@2 4!i$! emplo + M+ro@ $!+in Monte +rlo ?r+me4or (%7). mpute" *P4it! + miin'ne Q 1U; MA K 1U, or !o4in' "ep+rture ?rom H+r"–einber'eDuilibrium in $ontrol (K1 10%) 4ere eL$lu"e". *ubeDuent tet o? +o$i+tion 4ere per?orme" uin' *Ptet@2 4!i$! t+e 'enotpe improb+bilit into +$$ount 4!en$omp+rin' impute" 'enotpe (%8).

&tatistical analysis

#+t+ m+nipul+tion +n" t+titi$ 4ere per?orme" uin' P3 (%9). o!ort o? @-#, -#, Germ+n -#, i+tro'eni$ -# +n" uru reit+nt 4omen 4ere $omp+re" 4it!rele@+nt $ontrol uin' +lleli$ +n" 'enotpi$ mo"el. A'e +t "e+t! (or +mplin') 4+ ue"+ + Du+ntit+ti@e tr+it in +n+li o? uru p+tient. A'e +t $lini$+l onet eLpree" +"e@i+tion ?rom t!e me+n eLpe$te" onet ?or e+$! P# mut+tion 4+ ue" + + Du+ntit+ti@etr+it in t!e P# $o!ort. Met++n+le 4ere "one uin' P3 ?or +ll -#, +ll -#,+ll -# +n" +ll -# in$lu"in' reit+n$e to uru. mput+tion 4+ "one uin' MP2uin' "+t+ pro@i"e" b t!e +n" 1000 'enome proe$t. on"ition+l +n+le4ere "one +t t!e PRNP lo$u uin' r1799990 in +""iti@e +n" 'enotpi$ mo"el.*tr+ti?ie" +n+le 4ere "one uin' +ll t!ree 'enotpe +t r1799990. A'e o? $lini$+l

onet in -# 4+ ue" eit!er + + Du+ntit+ti@e tr+it or + + t!re!ol" ?or tr+ti?i$+tion(in$lu"e onl -# +'e +t onet K60 e+r). e per?orme" + permut+tion +n+li toe@+lu+te t!e i'ni?i$+n$e o? ober@in' n *P 4it! P K 105, 4!en +pproLim+tel ?i@eu$! *P 4ere eLpe$te" un"er t!e null !pot!ei. +e–$ontrol l+bel 4ere permute"4it!in e+$! o? t!e ?our $o!ort, +n" + 'enome4i"e met++n+li 4+ per?orme" on t!e permute" "+t+ et uin' t!e +me +n+li + ?or t!e ober@e" "+t+ et. !i 4+ repe+te"500 time 'ener+tin' $ru"e etim+te ?or t!e i'ni?i$+n$e o? t!i t+titi$ (ee eult). oimpro@e on t!i etim+te, 4e ?itte" + '+mm+Poion "itribution (+lo no4n + t!ene'+ti@e binomi+l) to t!e 500 $ount o? i'ni?i$+nt *P b m+t$!in' t!e empiri$+l me+n+n" @+ri+n$e to t!eir t!eoreti$+l @+lue (met!o" o? moment etim+tion). Alt!ou'! t!e$!oi$e o? 105 + + i'ni?i$+n$e t!re!ol" ?or t!i +n+li i +rbitr+r, it i + n+tur+l

$!oi$e +n" t!e onl one 4e $oni"ere" o 4e !+@e not implemente" +n ?orm+l$orre$tion ?or multiple tetin'. e etim+te" t!e e??e$ti@e number o? in"epen"ent tetuin' impleM (>0).

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&#PP'%*%NTA2 *AT%IA'













*upplement+r M+teri+l i +@+il+ble +t HMG online.

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3#N"ING

un"in' ?or t!e proe$t 4+ pro@i"e" b t!e ell$ome rut +n" Me"i$+l ee+r$!oun$il. !e uru tu"ie 4ere initi+ll ?un"e" b + ell$ome rut Prin$ip+l ee+r$!ello4!ip in t!e lini$+l *$ien$e to -.., +n" in$e 2001, +ll ot!er +pe$t o? t!e 4or b t!e Me"i$+l ee+r$! oun$il. *ome o? t!i 4or 4+ un"ert+en +t 3H&3 4!ore$ei@e" + proportion o? ?un"in' ?rom t!e #ep+rtment o? He+lt!N H /iome"i$+lee+r$! entre ?un"in' $!eme.

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&upplementary *aterial&upplementary "ata4 li$ !ere to @ie4.Go to:

A$/N!5'%"G%*%NT&

!i tu" m+e ue o? "+t+ 'ener+te" b t!e ell$ome rut +eontrol onortium.A ?ull lit o? t!e in@eti'+tor 4!o $ontribute" to t!e 'ener+tion o? t!e "+t+ i +@+il+ble?rom 444.4t$$$.or'.u . e 4oul" lie to t!+n p+tient, t!eir ?+milie +n" $+rer,

neurolo'it +n" ot!er re?errin' p!i$i+n, $o4orer +t t!e +tion+l Prion lini$, our$olle+'ue +t t!e +tion+l reut<?el"t-+ob #ie+e ee+r$! +n" *ur@eill+n$e nit,"inbur'!, +n" t!e ore $ommunitie in PG. e t!+n our te+m o? lo$+l uru reporter,in$lu"in' uli Anu+, Au+n+ in+'+i+, t!e l+te Anu+ *en+@+io, '+n+ Are+'u, +bin+Y+r+i, An"eron Pu4+, #+@i" P+o, Pibi Au+n+, -ol+m E@e, -+$ ointo, #+t+ Hutu+n" -+me i+@+. e +re 'r+te?ul to Ant!on -+$on +n" Peter *ib+, -o!n ee"er,!+rle M'one +n" ot!er t+?? o? t!e PG ntitute o? Me"i$+l ee+r$! ?or t!eir upport.e 'r+te?ull +$no4le"'e t!e !elp o? t!e l+te +rleton G+"ue, t!e l+te -oep! Gibb+n" t!eir +o$i+te ?rom t!e ?ormer 3+bor+tor o? entr+l er@ou *tem *tu"ie o? t!e +tion+l ntitute o? He+lt!, /et!e"+, *A, ?or +r$!i@in' +n" !+rin' ol" uru +mple.Genotpe "+t+ 4ill be m+"e +@+il+ble t!rou'! t!e urope+n Genomep!enome Ar$!i@e.

Con!"#$% o In$&r&%$ %$'$&(&n$ . one "e$l+re".

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%3%%N$%&






http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313791/bin/supp_21_8_1897__index.html


http://www.wtccc.org.uk/





http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313791/bin/supp_21_8_1897__index.html


http://www.wtccc.org.uk/




1. ollin'e -. Prion "ie+e o? !um+n +n" +nim+l: t!eir $+ue +n" mole$ul+r b+i.Annu. e@. euro$i. 2001;2>:519–550. IPubMe"J2. ollin'e -., *i"le .., Me+" -., roni"e -., Hill A.. Mole$ul+r +n+li o? priontr+in @+ri+tion +n" t!e +etiolo' o? Wne4 @+ri+ntX -#. +ture. 1996;%8%:685–690.IPubMe"J

%. /ru$e M.., ill .G., roni"e -.., M$onnell ., #rummon" #., *uttie A.,M$+r"le 3., !ree A., Hope -., /irett ., et +l. r+nmiion to mi$e in"i$+te t!+tWne4 @+ri+ntX -# i $+ue" b t!e /* +'ent. +ture. 1997;%89:>98–501. IPubMe"J>. Hill A.., #ebrul+i M., -oiner *., *i"le ..3., Go4l+n" ., ollin'e -. !e +me prion tr+in $+ue @-# +n" /*. +ture. 1997;%89:>>8–>50. IPubMe"J5. ollin'e -., P+lmer M.*., #r"en A.-. Geneti$ pre"ipoition to i+tro'eni$ reut<?el"t– -+ob "ie+e. 3+n$et. 1991;%%7:1>>1–1>>2. IPubMe"J6. P+lmer M.*., #r"en A.-., Hu'!e -.., ollin'e -. Homo<'ou prion protein'enotpe pre"ipoe to por+"i$ reut<?el"t–-+ob "ie+e. +ture. 1991;%52:%>0–%>2.IPubMe"J7. Poulter M., /+er H.., rit! .#., 3e+$! M., 3o?t!oue ., i"le .M., *!+! .,

E4en ., ollin'e -., /ro4n -., et +l. n!erite" prion "ie+e 4it! 1>> b+e p+ir 'eneinertion: : 'ene+lo'i$+l +n" mole$ul+r tu"ie. /r+in. 1992;115:675–685. IPubMe"J8. ollin'e -. Mole$ul+r neurolo' o? prion "ie+e. -ourn+l o? eurolo' eurour'er+n" P$!i+tr. 2005;76:906–919. IPM ?ree +rti$leJ IPubMe"J9. Me+" *., !it?iel" -., Poulter M., *!+! P., p!ill -., +mpbell ., Al #u+il H.,Hummeri$! H., /e$ -., Mein .A., et +l. A no@el prote$ti@e prion protein @+ri+nt t!+t$olo$+li<e 4it! uru eLpoure. . n'l. -. Me". 2009;%61:2056–2065. IPubMe"J10. *!ibu+ *., Hi'u$!i -., *!in .., +tei!i -., it+moto . Prote$ti@e prion protein polmorp!im +'+int por+"i$ reut<?el"t–-+ob "ie+e. 3+n$et. 1998;%51:>19.IPubMe"J11. *tep!enon #.A., !iotti ., belin' ., Grot! #., #eArmon" *.-., Pruiner *./.,+rlon G.A. Ou+ntit+ti@e tr+it lo$i +??e$tin' prion in$ub+tion time in mi$e. Genomi$.2000;69:>7–5%. IPubMe"J12. 3lo" *., En4u+<or E.., /e$ -., M+llinon G., +rr+ll M., +r'oni P., ollin'e-., i!er . "enti?i$+tion o? multiple Du+ntit+ti@e tr+it lo$i line" to prion "ie+ein$ub+tion perio" in mi$e. Pro$. +tl A$+". *$i. *A. 2001;98:6279–628%. IPM ?ree+rti$leJ IPubMe"J1%. 3lo" *., p!ill -./., +r'oni P.=., i!er ., ollin'e -. "enti?i$+tion o? 'eneti$lo$i +??e$tin' moue+"+pte" bo@ine pon'i?orm en$ep!+lop+t! in$ub+tion time in mi$e. euro'eneti$. 2002;>:77–81. IPubMe"J1>. Me+" *., Poulter M., p!ill -., /e$ -., !it?iel" -., ebb .., +mpbell .,A"+mon G., #eri<ioti P., +bri<i *.-., et +l. Geneti$ ri ?+$tor ?or @+ri+nt reut<?el"t– -+ob "ie+e: + 'enome4i"e +o$i+tion tu". 3+n$et eurol. 2009;8:57–66. IPM?ree +rti$leJ IPubMe"J15. /e$ -.A., +mpbell ., A"+mon G., Poulter M., p!ill -., Molou ., ollin'e -.,Me+" *. Ao$i+tion o? + null +llele o? *P 4it! @+ri+nt reut<?el"t–-+ob "ie+e. -.Me". Genet. 2008;>5:81%–817. IPM ?ree +rti$leJ IPubMe"J16. 3lo" *.., M+t!+m .G., Pot+ H., Gri<eno@+ -., Molou ., p!ill -., Hummeri$!H., !it?iel" -., Alper M.P., Me+" *., ollin'e -. H#2 i +o$i+te" 4it!

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., euen$!4+n"er A., Abr+mo4i #., re P., -+ton A.3., et +l. Lo'enou in"u$tiono? $erebr+l bet++mloi"o'enei i 'o@erne" b +'ent +n" !ot. *$ien$e.2006;%1%:1781–178>. IPubMe"J19. H+rol" #., Abr+!+m ., Hollin'4ort! P., *im ., Gerri! A., H+m!ere M.3., P+!4+-.*., Mo@in+ =., #o4<ell ., illi+m A., et +l. Genome4i"e +o$i+tion tu"i"enti?ie @+ri+nt +t 3 +n" PA3M +o$i+te" 4it! Al<!eimerX "ie+e. +t. Genet.2009;>1:1088–109%. IPM ?ree +rti$leJ IPubMe"J20. =+n #eerlin =.M., *leim+n P.M.A., M+rtine<3+'e M., !enPlotin A., +n' 3.*.,Gr+??+"?or" .., #i$on #.., +"em+er ., /oe@e /.., Grom+n M., et +l.ommon @+ri+nt +t 7p21 +re +o$i+te" 4it! ?rontotempor+l lob+r "e'ener+tion 4it!#P>% in$luion. +t. Genet. 2010;>2:2%>–2%9. IPM ?ree +rti$leJ IPubMe"J

21. *imon*+n$!e< -., *$!ulte ., /r+ -.M., *!+rm+ M., Gibb -.., /er' #., P+i+nui< ., 3i$!tner P., *$!ol< *.., Hern+n"e< #.G., et +l. Genome4i"e +o$i+tion tu"re@e+l 'eneti$ ri un"erlin' P+rinonX "ie+e. +t. Genet. 2009;>1:1%08–1%12.IPM ?ree +rti$leJ IPubMe"J22. *!+tuno@ A., Mo ., e4!oue *., e+le M.., *mit! /., =+n$e ., -o!non 3.,=el"in -.H., @+n M.A., @+n "en /er' 3.H., et +l. !romoome 9p21 in por+"i$+motrop!i$ l+ter+l $leroi in t!e +n" e@en ot!er $ountrie: + 'enome4i"e+o$i+tion tu". 3+n$et eurolo'. 2010;9:986–99>. IPM ?ree +rti$leJ IPubMe"J2%. !e ell$ome rut +e ontrol onortium. Genome4i"e +o$i+tion tu" o?1>,000 $+e o? e@en $ommon "ie+e +n" %,000 !+re" $ontrol. +ture.2007;>>7:661–678. IPM ?ree +rti$leJ IPubMe"J2>. Me+" *., !it?iel" -., Poulter M., *!+! P., p!ill -., /e$ -., +mpbell ., Al #u+ilH., Hummeri$! H., Alper M.P., ollin'e -. Geneti$ u$eptibilit, e@olution +n" t!e uruepi"emi$. P!ilo. r+n. . *o$. 3on". / /iol. *$i. 2008;%6%:%7>1–%7>6. IPM ?ree+rti$leJ IPubMe"J25. Me+" *., Poulter M., /e$ -., ebb ., +mpbell ., 3ine!+n -., #ebrul+i M.,-oiner *., +"4ort! -.#., in' A., et +l. n!erite" prion "ie+e 4it! iL o$t+pepti"erepe+t inertion+l mut+tion–mole$ul+r +n+li o? p!enotpi$ !etero'eneit. /r+in.2006;129:2297–2%17. IPubMe"J26. ebb .., Poulter M., /e$ -., p!ill -., A"+mon G., +mpbell ., 3ine!+n -.,Po4ell ., /r+n"ner *., P+l *., et +l. P!enotpi$ !etero'eneit +n" 'eneti$ mo"i?i$+tiono? P1023 in!erite" prion "ie+e in +n intern+tion+l erie. /r+in. 2008;1%1:26%2–26>6.IPM ?ree +rti$leJ IPubMe"J27. ebb ..., !itt+er -., ollin'e -., Me+" *. A'e o? onet +n" "e+t! in in!erite" prion "ie+e +re !erit+ble. Am. -. Me". Genet. / europ$!i+tr. Genet.2009;150/:>96–501. IPubMe"J28. Me+" *., M+!+l *.P., /e$ -., +mpbell ., +rr+ll M., i!er ., ollin'e -. *por+"i$ ]but not @+ri+nt]reut<?el"t–-+ob "ie+e i +o$i+te" 4it! polmorp!im uptre+mo? PRNP Lon 1. Am. -. Hum. Genet. 2001;69:1225–12%5. IPM ?ree +rti$leJ IPubMe"J



















































29. M$orm+$ -.., /+butt H.., @erin'ton #., ill .G., roni"e -.., M+non -..PP $ont+in bot! introni$ +n" uptre+m re'ul+tor re'ion t!+t m+ in?luen$eu$eptibilit to reut<?el"t–-+ob "ie+e. Gene. 2002;288:1%9–1>6. IPubMe"J%0. =ollmert ., in"l E., î+n' ., oenber'er A., err ., i$!m+nn H..,/i$eboller H., lli' ., ret<$!m+r H.A. *i'ni?i$+nt +o$i+tion o? + M129=

in"epen"ent polmorp!im in t!e 5_ o? t!e PP 'ene 4it! por+"i$ reut<?el"t– -+ob "ie+e in + l+r'e Germ+n $+e$ontrol tu". -. Me". Genet. 2006;>%:e5%. IPM?ree +rti$leJ IPubMe"J%1. Hill A.., -oiner *., +"4ort! -.#., *i"le .., /ell -.., /u"+ H., roni"e -..,ollin'e -. Mole$ul+r $l+i?i$+tion o? por+"i$ reut<?el"t–-+ob "ie+e. /r+in.200%;126:1%%%–1%>6. IPubMe"J%2. ollin'e -., l+re A. A 'ener+l mo"el o? prion tr+in +n" t!eir p+t!o'eni$it.*$ien$e. 2007;%18:9%0–9%6. IPubMe"J%%. Gu"b+rton #.., +lter G./., !orlei?on G., *te?+non H., H+ll"oron /.=.,um+no@i$! P., *ulem P., !orl+$iu *., Gl?+on A., *teinber' *., et +l. M+n eDuen$e@+ri+nt +??e$tin' "i@erit o? +"ult !um+n !ei'!t. +t. Genet. 2008;>0:609–615.

IPubMe"J%>. ebb .., P+l *., *i""iDue #., He+ne #.., 3ine!+n -.M., +"4ort! -.#., -oiner*., /e$ -., roe *.-., *te@enon =., et +l. irt report o? reut<?el"t–-+ob "ie+eo$$urrin' in 2 iblin' uneLpl+ine" b PP mut+tion. -. europ+t!ol. Lp. eurol.2008;67:8%8–8>1. IPubMe"J%5. +r" H.-., @erin'ton #., ouen *.., *mit!/+t!'+te /., Gillie M., Murr+ .,ni'!t .*., *mit! P.G., ill .G. i ?+$tor ?or por+"i$ reut<?el"t–-+ob "ie+e.Ann. eurol. 2008;6%:%>7–%5>. IPubMe"J%6. #e@lin /., oe"er . Genomi$ $ontrol ?or +o$i+tion tu"ie. /iometri$.1999;55:997–100>. IPubMe"J%7. Ho4ie /.., #onnell P., M+r$!ini -. A ?leLible +n" +$$ur+te 'enotpe imput+tionmet!o" ?or t!e neLt 'ener+tion o? 'enome4i"e +o$i+tion tu"ie. P3o* Genet.2009;5:e1000529. IPM ?ree +rti$leJ IPubMe"J%8. M+r$!ini -., Ho4ie /., Mer *., M$=e+n G., #onnell P. A ne4 multipoint met!o"?or 'enome4i"e +o$i+tion tu"ie b imput+tion o? 'enotpe. +t. Genet.2007;%9:906–91%. IPubMe"J%9. Pur$ell *., e+le /., o""/ro4n ., !om+ 3., erreir+ M.A.., /en"er #., M+ller-., *l+r P., "e /+er P..., #+l M.-., *!+m P.. P3: + tool et ?or 4!ole'enome+o$i+tion +n" popul+tionb+e" lin+'e +n+le. Am. -. Hum. Genet. 2007;81:559– 575. IPM ?ree +rti$leJ IPubMe"J>0. G+o ^.Y., /e$er 3.., /e$er #.M., *t+rmer -.#., Pro@in$e M.A. A@oi"in' t!e !i'!/on?erroni pen+lt in 'enome4i"e +o$i+tion tu"ie. Genet. pi"emiol. 2010;%>:100– 105. IPM ?ree +rti$leJ IPubMe"J

Jurnal 6/r+in. 2010 E$tober; 1%%(10): %0%0–%0>2.Publi!e" online 2010 *eptember 7. "oi: 10.109%&br+in&+4D2%>PM#: PM29>7>29


















http://dx.doi.org/10.1093%2Fbrain%2Fawq234





















Agent strain 7ariation in human prion

disease4 insights from a molecular and

pathological re7iew of the NationalInstitutes of +ealth series of

e8perimentally transmitted disease

Piero P+r$!i, 1 M+ur+ e$+tti,1 *il@io ot+ri,1 +lter -. *$!ul<*$!+e??er ,2 *+bin++pell+ri,1 Armin Giee,% enOu+n ou,> H+n ret<$!m+r ,% /ern+r"ino G!etti,5 +n"P+ul /ro4n6

Aut!or in?orm+tion C Arti$le note C opri'!t +n" 3i$ene in?orm+tion C!i +rti$le !+ been $ite" b ot!er +rti$le in PM.

Go to:

Abstract

*iL $lini$op+t!olo'i$+l p!enotpe o? por+"i$ reut<?el"t–-+ob "ie+e !+@e been$!+r+$teri<e" 4!i$! $orrel+te +t t!e mole$ul+r le@el 4it! t!e tpe (1 or 2) o? t!e +bnorm+l prion protein, PrP*, preent in t!e br+in +n" 4it! t!e 'enotpe o? polmorp!i$(met!ionine or @+line) $o"on 129 o? t!e prion protein 'ene. Ho4e@er, to 4!+t eLtentt!ee p!enotpe 4it! t!eir $orrepon"in' mole$ul+r $ombin+tion (i.e. MM1, MM2,==1 et$.) en$ip!er "itin$t prion tr+in upon tr+nmiion rem+in un$ert+in. e tu"ie"t!e PrP* tpe +n" t!e prion protein 'ene in +r$!i@+l br+in tiue ?rom t!e +tion+l

ntitute o? He+lt! erie o? tr+nmitte" reut<?el"t–-+ob "ie+e +n" uru $+e, +n"$!+r+$teri<e" t!e mole$ul+r +n" p+t!olo'i$+l p!enotpe in t!e +??e$te" non!um+n prim+te, in$lu"in' Duirrel, pi"er, $+pu$!in +n" A?ri$+n 'reen mone. e ?oun" t!+tt!e tr+nmiion propertie o? prion ?rom t!e $ommon por+"i$ reut<?el"t–-+ob"ie+e MM1 p!enotpe +re !omo'eneou +n" i'ni?i$+ntl "i??er ?rom t!oe o? por+"i$reut<?el"t–-+ob "ie+e ==2 or M=2 prion. Anim+l ine$te" 4it! i+tro'eni$reut<?el"t–-+ob "ie+e MM1 +n" 'eneti$ reut<?el"t–-+ob "ie+e MM1 line" tot!e 200 mut+tion !o4e" t!e +me p!enotpi$ ?e+ture + t!oe in?e$te" 4it! por+"i$reut<?el"t–-+ob "ie+e MM1 prion, 4!ere+ uru mot $loel reemble" t!epor+"i$ reut<?el"t–-+ob "ie+e ==2 or M=2 prion i'n+ture +n" neurop+t!olo'.!e ?in"in' in"i$+te t!+t t4o "itin$t prion tr+in +re line" to t!e t!ree mot $ommon

reut<?el"t–-+ob "ie+e $lini$op+t!olo'i$+l +n" mole$ul+r ubtpe +n" uru, +n"u''et t!+t uru m+ !+@e ori'in+te" ?rom $+nnib+liti$ tr+nmiion o? + por+"i$reut<?el"t–-+ob "ie+e o? t!e ==2 or M=2 ubtpe.

/eywords4 prion "ie+e, neurop+t!olo', neuro"e'ener+ti@e "ior"er, p!enotpe,tr+in tpin'Go to:

http://www.ncbi.nlm.nih.gov/pubmed/?term=Parchi%20P%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Cescatti%20M%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Notari%20S%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Schulz-Schaeffer%20WJ%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Capellari%20S%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Giese%20A%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Zou%20WQ%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Ghetti%20B%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Brown%20P%5Bauth%5D









http://www.ncbi.nlm.nih.gov/pubmed/?term=Parchi%20P%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Cescatti%20M%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Notari%20S%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Schulz-Schaeffer%20WJ%5Bauth%5D




http://www.ncbi.nlm.nih.gov/pubmed/?term=Zou%20WQ%5Bauth%5D



http://www.ncbi.nlm.nih.gov/pubmed/?term=Brown%20P%5Bauth%5D









Introduction

r+nmiible pon'i?orm en$ep!+lop+t!ie (*) or prion "ie+e +re in@+ri+bl ?+t+lneuro"e'ener+ti@e "ior"er +??e$tin' !um+n +n" ot!er m+mm+l u$! + !eep, "eer,el +n" $+ttle. n !um+n, * o$$ur 4orl"4i"e + por+"i$, 'eneti$ or +$Duire" "ie+e

+n" $omprie t!ree m+or "ie+e entitie 4it! @+ri+ble t!ou'! o@erl+ppin' p!enotpe:reut<?el"t–-+ob "ie+e (-#), Gertm+nn–*trùler–*$!einer n"rome +n" ?+t+linomni+. n +""ition, t!e term )*r* !+ been +ttribute" to +n +$Duire" !um+n prion"ie+e ?+llin' 4it!in t!e p!enotpi$ pe$trum o? -# t!+t +??e$te" prim+ril t!e orelin'uiti$ 'roup o? t!e +tern Hi'!l+n" o? P+pu+ e4 Guine+.

n *, +n +bnorm+l, bet+!eet ri$! +n" p+rti+ll prote+ereit+nt io?orm (PrP*) o?t!e $ellul+r prion protein, PrP, +$$umul+te in t!e ner@ou tem, +n" to + leer eLtentin ot!er or'+n, +n" repreent t!e !+llm+r o? t!e "ie+e (/ro4n &$ '!., 1986; obert &$

'!., 1986). !e $on@erion o? PrP to PrP* i + pottr+nl+tion+l e@ent, +n" in@ol@e +$on?orm+tion+l $!+n'e o? t!e protein (+u'!e &$ '!., 1991; P+n &$ '! ., 199%) t!+t $+n be

tr+nmitte" b +n +uto$+t+lti$ me$!+nim (/ie$!e &$ '!., 200>). PrP* i t!ou'!t to be+n eenti+l, i? not t!e eL$lui@e, $omponent o? t!e tr+nmiible +'ent, or prion(Pruiner, 1998; eim+nn, 200>; A'u<<i &$ '!., 2008).

Prion "ie+e $omprie + bro+" pe$trum o? $lini$op+t!olo'i$+l p!enotpe t!+t !o4!etero'eneit in "ie+e "ur+tion, mptom+tolo' +n" "itribution o? br+in leion u$!+ pon'ioi, neuron+l lo +n" 'lioi, + 4ell + preen$e +n" morp!olo' o? +mloi" pl+Due (G+mbetti &$ '!., 200%; G!etti &$ '!., 200%; ret<$!m+r +n" P+r$!i, 2007).#i??erent prion tr+in +re belie@e" to be t!e m+in $+ue o? * p!enotpi$ "i@erit(A'u<<i &$ '!., 2007). * tr+in 4ere ori'in+ll "e?ine" b t!eir "itin$t "ie+e p!enotpe upon tr+nmiion to n'eni$ +nim+l, 4!i$! perit on eri+l tr+nmiion

(r+er &$ '!., 197%; /ru$e &$ '!., 1991). it!in + 'i@en !ot pe$ie, prion tr+in "i??erm+inl in t!eir in$ub+tion time, t!e "itribution o? $entr+l ner@ou tem @+$uol+tiont!+t t!e pro"u$e +n" 4!et!er or not t!e in"u$e +mloi" pl+Due. n +""ition, t!e !ot'enotpe @+ri+bilit in t!e 'ene en$o"in' PrP ( PRNP ), + "etermine" b polmorp!imor mut+tion, !+ +lo been re$o'ni<e" + + $+u+l ?+$tor ?or p!enotpi$ !etero'eneit(/ru$e &$ '!., 1991; P+lmer &$ '!., 1991; Gol"?+rb &$ '!., 1992; Gol"m+n &$ '!., 199>;/+rron &$ '! ., 2001; G+mbetti &$ '!+ , 200%; G!etti &$ '!., 200%). #itin$t !um+n tr+in o?t!e prion +'ent !+@e been "emontr+te" +?ter eLperiment+l tr+nmiion (ellin' &$ '!.,1996; /ru$e &$ '!., 1997; Hill &$ '!., 1997; 3+me<+ &$ '!., 2001; ort! &$ '!., 200%; onno &$ '!., 2005; /i!op &$ '!., 2006; ob++!i &$ '!., 2010) but rem+in to be ?ull$!+r+$teri<e".

n$ert+intie +lo rem+in re'+r"in' t!e mole$ul+r b+i o? * tr+in +n" t!erel+tion!ip bet4een t!e +'ent tr+in +n" PrP (A'u<<i &$ '!., 2007). #itin$t PrP* pro?ile or tpe !+@e been ?oun" in bot! !um+n +n" +nim+l +n" $+n be "itin'ui!e" b pe$i?i$ p!i$o$!emi$+l propertie u$! + i<e +?ter prote+e tre+tment, "e'ree o? prote+e reit+n$e, +n" $on?orm+tion+l t+bilit +n" 'l$o?orm r+tio (+$+ &$ '!+ ,1986; /een +n" M+r!, 199>; Mon+ri &$ '!+ , 199>; ollin'e &$ '!., 1996; P+r$!i &$ '!+ ,1996, 1997, 2000; *omer@ille &$ '!., 1997; *+?+r &$ '!., 1998; ot+ri &$ '!., 200>; /+ron &$

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'!., 2007; em!euer &$ '!., 2009). !e "i??erent PrP* tpe $+n be +o$i+te" 4it!"itin$t "ie+e p!enotpe e@en in ube$t 4it! t!e +me PRNP 'enotpe (P+r$!i &$ '!.,1999, 2000). urt!ermore, it !+ been !o4n t!+t propertie o? t!e PrP* tpe rel+te" to protein $on?orm+tion, u$! + t!e i<e o? t!e prote+ereit+nt $ore, +re o?ten m+int+ine"+?ter interpe$ie tr+nmiion (ellin' &$ '!, 1996), +lt!ou'! $!+n'e m+ +lo o$$ur in

$ert+in re$ipient 'enotpe (Hill &$ '!., 1997; ob++!i &$ '!., 2010). n umm+r,$ir$umt+nti+l e@i"en$e u''et t!+t t!e tr+in p!enotpe +re en$ip!ere" in "itin$tterti+r or e@en Du+tern+r tru$ture o? PrP*, +lt!ou'! t!e ?orm+l proo? i till +bent.Gi@en t!ee un$ert+intie +n" to +@oi" $on?uion, t!rou'!out t!i m+nu$ript t!e term pr"on %$r'"n i ue" to re?er to t!e propert o? t!e prion +'ent to in"u$e + pe$i?i$ "ie+e p!enotpe in + 'i@en !ot 'enotpe +?ter tr+nmiion, 4!ere+ t!e term PrP* tpere?er to onl t!e bio$!emi$+l PrP* propertie, uu+ll "e?ine" b 4etern blottin', t!+t!+@e been +o$i+te" 4it! + 'i@en "ie+e p!enotpe.

4o m+or !um+n PrP* tpe +re no4n, 4!i$! !+@e been eLteni@el repro"u$e"+mon' l+bor+torie: Wtpe 1X 4it! + rel+ti@e mole$ul+r m+ o? t!e prote+ereit+nt $ore

o? 21 #+ +n" t!e prim+r $le+@+'e ite +t rei"ue 82, +n" Wtpe 2X 4it! + rel+ti@emole$ul+r m+ o? 19 #+ +n" t!e prim+r $le+@+'e ite +t rei"ue 97 (P+r$!i &$ '!+ , 1996,1997, 2000).

PrP* tpe 1 +n" 2, in $onun$tion 4it! t!e 'enotpe +t t!e met!ionine (M) & @+line (=) PRNP $o"on 129, l+r'el $orrel+te 4it! p!enotpi$ @+ri+bilit in !um+n por+"i$ *+n" pro@i"e + mole$ul+r b+i ?or "ie+e $l+i?i$+tion (i.e. MM1, MM2, ==1, et$.)(P+r$!i &$ '!., 1996, 1999). urt!ermore, t!e +me !um+n PrP* tpe "ete$te" inpor+"i$ * 4ere +lo ?oun" to be +o$i+te" 4it! "itin$t p!enotpe in i+tro'eni$-#, uru +n" ?+mili+l -# (P+r$!i &$ '!., 1997, 2000), t!u r+iin' t!e poibilit t!+tt!e +me prion tr+in 4oul" be iol+te" upon tr+nmiion ?rom +ll t!ee * ?orm,

in"epen"ent o? t!eir +pp+rentl "i??erent +etiolo'.

!e eLperiment+l tr+nmiion o? -# +n" uru 4+ ?irt +$$ompli!e" in t!e 1960t!rou'! t!e pioneerin' tu"ie o? G+"ue, Gibb +n" Alper +t t!e +tion+l ntitute o? He+lt! (H) (G+"ue &$ '!., 1966; Gibb &$ '!., 1968). !i 'roun"bre+in' "i$o@erle" to +n inteni@e %0e+r ree+r$! pro'r+mme "urin' 4!i$! e@er+l !un"re" o? $+eo? @+riou neurolo'i$+l "ior"er 4ere ino$ul+te" in non!um+n prim+te. lini$+l,neurop+t!olo'i$+l +n" biolo'i$+l "+t+ $on$ernin' t!ee tr+nmiion !+@e been publi!e" but !+@e not in$lu"e" tu"ie to i"enti? "itin$t p!enotpe b me+n o? leion pro?ilin' or mole$ul+r $!+r+$teri<+tion o? PrP* b 4etern blottin', PrPimmuno!ito$!emitr +n" p+r+??in embe""e" tiue (P) blottin'. e +""re !ere t!eiue o? prion tr+in @+ri+tion in !um+n * +n" t!eir mole$ul+r b+i, 4it! +tem+ti$ re+n+li o? "ie+e $!+r+$teriti$ in m+t$!e" !um+n +n" non!um+n prim+te tiue obt+ine" ?rom t!e H erie o? tr+nmitte" $+e, 4!i$! pro@i"e +!itori$+ll uniDue reour$e to tu" t!e iue o? !um+n prion tr+in in + $ompre!eni@eerie o? tr+nmiion to prim+te.

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*aterials and methods

$ase and tissue selection

+uman cases

A tot+l o? 99 !um+n $+e 4ere ele$te" ?rom t!e H "+t+b+e o? tr+nmitte" * b+e" on t!e +@+il+bilit o? ?ro<en tiue. n +""ition, 1% tr+nmitte" uru $+e 4ereele$te" "epite t!e l+$ o? ?ro<en tiue. A$$or"in' to t!e ori'in+l $lini$op+t!olo'i$+l+n" 'eneti$ +n+le obt+ine" ?rom t!e H "+t+b+e +n" pre@iou publi$+tion (/e$ &$

'!., 197%; *$rim'eour &$ '!., 198%; /ro4n &$ '!., 1986, 199>; Gol"?+rb &$ '!., 1991;er@enao@a &$ '!., 1998), t!e ele$te" $+e $onite" o? 90 por+"i$ -#, 5 ?+mili+l-# $+rrin' t!e 200 mut+tion $ouple" 4it! met!ionine +t $o"on 129 in bot! mut+te"+n" 4il"tpe +llele (200129MM), 2 i+tro'eni$ -# reultin' ?rom $ont+min+te"tereot+$ti$ intr+$erebr+l G nee"le (/ernoulli &$ '!., 1977) +n" 15 uru $+e. All$+e !+" + neurop+t!olo'i$+ll @eri?ie" pon'i?orm en$ep!+lop+t!, +n" in 99 $+e, t!e

"i+'noi 4+ $on?irme" b 4etern blottin' (+ll but 1% uru $+e).

$linical analysis

lini$+l "+t+ ?or t!e !um+n * $+e 4ere +@+il+ble in +ll $+e, +n" to + l+r'e eLtentin$lu"e" in + pre@iou publi$+tion (/ro4n &$ '!., 199>).

n$ub+tion time ?rom ino$ul+tion to t!e onet o? $lini$+l mptom +n" t!e "ur+tion o?mptom ?or t!e non!um+n prim+te 4ere "r+4n ?rom H $!+rt +n" pre@ioul publi!e" "+t+ (/ro4n &$ '!., 199>). or t!ee +n+le, 4e $oni"ere" +nim+l t!+t 4ereino$ul+te" intr+$erebr+ll 4it! + 5–20U p!op!+te bu??ere" +line upenion o? ?re!

?ro<en br+in tiue. e +pplie" t!i $riterion 4it! t!e +im to eL$lu"e t!e le+t number o?+nim+l, in$e it 4+ pre@ioul ?oun" (/ro4n &$ '!., 199>) in eri+l "ilution eLperimentt!+t t!e len't! o? in$ub+tion time "oe not $!+n'e i'ni?i$+ntl in t!e 10 or 100 ?ol""ilution r+n'e, 4!ile it i i'ni?i$+ntl prolon'e" +t + 105 "ilution. urt!ermore, it !oul" be $oni"ere" t!+t mot o? t!e +nim+l in$lu"e" in t!e +n+le 4ere eLpoe" to + 10U!omo'en+te, +n" t!e rel+ti@e proportion o? +nim+l ine$te" 4it! + 5, 10 or 20U br+in!omo'en+te +mon' t!e mot i'ni?i$+nt 'roup o? +nim+l 4+ @er imil+r (e.'. 5, 77+n" 18U, repe$ti@el, ?or t!e 'roup o? Duirrel mone ine$te" 4it! por+"i$ -#MM1 +n" 17, 71 +n" 12U, repe$ti@el, ?or t!e Duirrel mone ine$te" 4it! por+"i$-# ==2).

/ei"e t!e $on$entr+tion, t!e @olume o? t!e ino$ul+te" !omo'en+te +lo @+rie", but t!im+inl +$$or"e" 4it! t!e i<e (pe$ie) o? prim+te: $!imp+n<ee (not in$lu"e" in t!e preent tu"), ?or eL+mple, routinel re$ei@e" 0.1 ml, 4!ere+ Duirrel mone uu+llre$ei@e" 0.05 ml (P. /ro4n, peron+l $ommuni$+tion). E@er+ll, + tot+l o? 1%0tr+nmiion eLperiment 4ere $oni"ere" ?or t!e $+l$ul+tion o? in$ub+tion time.

Primate brain tissues











































A?ter $reenin' t!e H +nim+l "+t+b+e, +ll poiti@e (i.e. neurop+t!olo'i$+ll @eri?ie"pon'i?orm en$ep!+lop+t!) +nim+l t!+t !+" been ino$ul+te" 4it! one o? t!e ele$te"!um+n * $+e, +n" ?or 4!i$! tiue (eit!er ?ro<en or ?iLe" or bot!) 4ere till+@+il+ble, 4ere +mple". iue ?rom ?our "i??erent non!um+n prim+te pe$ie (Duirrel,$+pu$!in, pi"er +n" A?ri$+n 'reen mone) 4+ obt+ine". o in$lu"e + m+n +nim+l

+ poible, +mplin' 4+ per?orme" irrepe$ti@e o? t!e +@+il+bilit o? t!e in?orm+tion onin$ub+tion time. !e rel+tion!ip bet4een number o? !um+n $+e +n+le" +n" t!enumber o? +nim+l +@+il+ble ?or t!e +n+le o? in$ub+tion time, !itop+t!olo'i$+l?e+ture +n" PrP* tpin' ?or t!e mot i'ni?i$+nt 'roup (i.e. Duirrel mone +t ?irt p++'e) i pro@i"e" in i'. 1A. !e l+r'e m+orit o? tiue 4ere obt+ine" ?rom +nim+line$te" +t ?irt p++'e; !o4e@er, ?iLe" tiue 4+ +lo t+en ?rom + 'roup o? Duirrelmone t!+t 4ere ine$te" eit!er +t e$on" p++'e or +?ter eri+l p++'e (i'. 1/).

i'ure 1(A) el+tion!ip bet4een number o? +nim+l +@+il+ble ?or t!e +n+le o? in$ub+tion time(/ M), !itop+t!olo'i$+l ?e+ture (PAH), +n" PrP* tpin' (PrP*) ?or t!el+r'et 'roup o? !um+n * ubtpe tr+nmitte" to Duirrel mone (?irt p++'e). )))

E@er+ll, ?ro<en tiue ?rom 100 prim+te 4+ +@+il+ble ?or PrP* tpin' +n+le, +n"?orm+lin ?iLe" tiue ?rom 9> +nim+l 4+ obt+ine" ?or neurop+t!olo'i$+l eL+min+tion.ro<en br+in tiue 4+ obt+ine" ?rom Duirrel (n F 72), $+pu$!in (n F 17), pi"er (n F 8)

+n" A?ri$+n 'reen (n F %) mone. 3+r'e tiue blo$ 4ere +@+il+ble in mot $+e (i.e.95U), 4!ere+ m+ll tiue ?r+'ment, uu+ll ?rom t!e $erebr+l $orteL, 4ere obt+ine"∼

?rom + ?e4 br+in. iue +mple ?or 4etern blot +n+le 4ere t+en ?rom t!e $erebr+l$orteL (uu+ll ?ront+l $orteL) in mot $+e; +mple ?rom t!e $erebellum +n" tri+tum4ere +""ition+ll obt+ine" in iL pi"er mone br+in.

iLe" br+in tiue 4+ obt+ine" ?rom Duirrel (n , 68, 50 +t ?irt p++'e +n" 18 +t e$on"or eri+l p++'e), pi"er (n , 11), $+pu$!in (n , 10) +n" A?ri$+n 'reen (n , 5) mone.!e tiue $onite" eit!er o? ?orm+lin ?iLe", p+r+??in embe""e" blo$ or ?orm+lin ?iLe" br+in li$e, or bot!. or e+$! $+e, "epen"in' on +@+il+bilit, e$tion 4ere obt+ine"?rom + m+n + poible o? t!e ?ollo4in' br+in re'ion: ?ront+l, tempor+l, p+riet+l +n"

o$$ipit+l $orti$e, !ippo$+mpu, entor!in+l $orteL, tri+tum, t!+l+mu, !pot!+l+mu,mi"br+in +n" $erebellum.

Neuropathology

*emiDu+ntit+ti@e e@+lu+tion o? pon'i?orm $!+n'e 4+ $+rrie" out uin' !+em+toLlin+n" eoin t+ine" e$tion. le@en br+in re'ion 4ere ele$te" ?or eL+min+tion (lite"+bo@e). *pon'i?orm $!+n'e 4+ $ore" on + 0–% $+le (not

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"ete$t+ble&mil"&mo"er+te&e@ere) +n" leion pro?ile 4ere obt+ine". !e leion pro?ile i+ 4ellet+bli!e" emiDu+ntit+ti@e met!o" o? me+urin' t!e t+r'etin' o? pon'i?orm$!+n'e to "i??erent br+in re'ion +n" reli+bl "i$rimin+te bet4een * tr+in in mi$e+n" ot!er pe$ie +n" bet4een por+"i$ -# ubtpe in !um+n (/ru$e &$ '!., 1996, 1997; P+r$!i &$ '!., 1999).

PrP immuno!ito$!emitr +n" P blot 4ere per?orme" u$$e?ull onl on p+r+??inembe""e" tiue blo$ (t!e lon't+n"in' ?orm+lin?iLe" tiue iel"e" ne'+ti@e reult, preum+bl "ue to t!e @er lon' tor+'e in ?orm+lin). iue ?rom %0 Duirrel mone(2> +t ?irt p++'e +n" 6 +t e$on" or eri+l p++'e) 4+ eL+mine" 4it! t!ee t4ote$!niDue. !e 2> +nim+l o? t!e ?irt 'roup 4ere ine$te" 4it! !omo'en+te ?rom:por+"i$ -# MM1 (n , 6), por+"i$ -# ==2 (n , 5), por+"i$ -# MM 4it! + 20 #+PrP*$ $ore (n , 1) (ee WeultX e$tion), por+"i$ -# M=2 4it! uru pl+Due (por+"i$-# M= 2) (n , 2), por+"i$ -# M=1 (n , 2), uru (n , %), i+tro'eni$ -# MM1 (n, 2) +n" ?+mili+l -# 200–129 M (n , %). !e 6 +nim+l o? t!e e$on" 'roup 4ereine$te" 4it! !omo'en+te ?rom por+"i$ -# MM1 (n , %) +n" uru (n , %). *t+inin'

4+ obt+ine" in +ll e$tion t!+t 4ere +@+il+ble ?or t!e !itop+t!olo'i$+l +n+li. P+r+??ine$tion ?rom ?orm+lin?iLe" blo$ 4ere pro$ee" uin' t!e mono$lon+l +ntibo"ie %>4it! epitope +t PrP rei"ue 108–111 +t 20 '&ml $on$entr+tion (*i'net 3+b, MA, *A)+$$or"in' to pre@ioul publi!e" proto$ol (P+r$!i &$ '!., 1996). PrP "epoit 4ere$l+i?ie" +$$or"in' to t!eir morp!olo' (i.e. n+pti$, 'r+nul+r, ?o$+l pl+Duelie). P blot 4+ per?orme" +$$or"in' to + pre@ioul "e$ribe" proto$ol (*$!ul<*$!+e??er &$ '!.,2000). L+min+tion o? t!e t+inin' p+ttern ?or bot! PrP immuno!ito$!emitr +n" P blot 4ere per?orme" blin" to t!e reult o? t!e mole$ul+r +n" !itop+t!olo'i$+l +n+li+n" t!e tpe o? !um+n ino$ulum.

Protein analysis

Prep+r+tion o? +mple in$lu"in' PrP* puri?i$+tion, 4etern blottin' +n" PrP* tpin'4ere per?orme" +$$or"in' to et+bli!e" met!o" ( ot+ri &$ '!., 200>, 2007; P+r$!i &$ '! .,2000, 2009'). n p+rti$ul+r, +ll +mple 4ere !omo'eni<e" in li bu??er plu I100mmol&l +l, 10 mmol&l #A, 0.5U (@&@) oni"et P >0, 0.5U (4&@) o"ium"eoL$!ol+te, 100 mmol&l ri–Hl, pH 6.9J +n" "i'ete" 4it! protein+e (o$!e#i+'noti$, pe$i?i$ +$ti@it b $erti?i$+te o? +n+li: >7.9 &m') +t + ?in+l$on$entr+tion o? 5 &ml. Puri?ie" PrP* 4+ obt+ine" ?rom +bout >00 m' o? tiue ?romt!e $erebr+l $orteL, 4!i$! 4+ ube$te" to t!ree $$le o? +rol eLtr+$tion +n""i??erenti+l $entri?u'+tion to iel" t!e P% pellet. unnin' 'el 4it! "i??erent ep+r+tin'"i$rimin+tor po4er (i.e. 5, 6.5 +n" 15 $m in len't!) 4ere ue". All +mple but t!oe

?rom $+pu$!in mone 4ere probe" 4it! t!e mono$lon+l +ntibo" %> (rei"ue 106– 110, *i'net 3+b, MA, *A) (+$+ &$ '!., 1986; ou &$ '!., 2010), 4!ere+ $+pu$!inmone !omo'en+te, 4!oe PrP i not re$o'ni<e" b %>, 4ere probe" 4it! t!emono$lon+l +ntibo" 9A2 (rei"ue 99–101). !e immunore+$ti@it 4+ @iu+li<e" ben!+n$e" $!emilumine$en$e (3 t+n"+r" or 3 Plu, G He+lt!$+re) on o"+/ioM+L 3i'!t ?ilm (+tm+n o"+ o.) +n" 4it! 3A*%000 $+mer+ (ui?ilm). oDu+nti? t!e PrP* $ontent, 4e $omp+re" t!e i'n+l intenit b "enitometr (Ai"+
















































m+'e An+l<er @.>.15 o?t4+re, +tet) 4it! + t+n"+r" $ur@e, obt+ine" b lo+"in' ine+$! 'el + eri+l "ilution (n , >) o? + por+"i$ -# +mple $!oen + t+n"+r".

*olecular genetic analysis

All !um+n +mple 4ere re+n+le", 4!ere+ t!e PRNP eDuen$e o? non!um+n prim+te 4+ obt+ine" ?rom pre@ioul publi!e" reult (er@enao@a &$ '!., 199>). nt!i re'+r" it i note4ort! t!+t +t @+ri+n$e 4it! !um+n, +ll non!um+n prim+te pe$ie$+rr met!ionine +t $o"on 129 (er@enao@a &$ '!., 199>). !e open re+"in' ?r+me o? t!e PRNP 4+ +mpli?ie" + pre@ioul "e$ribe", uin' #A puri?ie" ?rom br+in tiue(P+r$!i &$ '!., 1996). !e polmer+e $!+in re+$tion pro"u$t 4+ @iu+li<e" on + 1U+'+roe 'el to "ete$t potenti+l inertion mut+tion or "eletion. Potenti+l point mut+tion4ere initi+ll re@e+le" b +n+le b "en+turin' !i'!per?orm+n$e liDui"$!rom+to'r+p! +n" ubeDuentl $on?irme" b "ire$t eDuen$in' o? PRNP open re+"in'?r+me. in+ll, t!e $o"on 129 'enotpe 4+ eL+mine" b "i'etion 4it! t!e retri$tionen"onu$le+e p 1.

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esults

*olecular typing of human inocula

Mole$ul+r $l+i?i$+tion o? por+"i$, 'eneti$ +n" i+tro'eni$ -# +n" o? t4o uru $+e4+ per?orme" +$$or"in' to PrP* tpe (P+r$!i &$ '!., 1996, 1997, 1999) +n" PRNP 'enotpe. n +""ition, in?orm+tion re'+r"in' t!e $o"on 129 'enotpe 4+ +@+il+ble ?or 6out o? t!e 1% uru $+e l+$in' ?ro<en m+teri+l. Amon' t!em, > 4ere ==, 1 M= +n" 1MM. E@er+ll, t!e immunoblot +n+li o? PrP* ?rom t!e !um+n +mple 4+ $onitent4it! pre@ioul publi!e" "+t+. All but one +mple ?itte" 4it!in t!e pe$trum o? !um+nPrP* pro?ile pre@ioul "e$ribe" in por+"i$ -# (P+r$!i &$ '!., 1996, 1997; ot+ri &$

'!., 200>), $l+i$ i+tro'eni$ -# 4it! MM 'enotpe (P+r$!i &$ '!., 1997), ?+mili+l -#(Mon+ri &$ '!., 199>; P+r$!i &$ '!., 2000) +n" uru (P+r$!i &$ '!., 1997). n p+rti$ul+r, t!et4o uru $+e 4it! ?ro<en tiue 4ere == +n" M= +t $o"on 129 +n" !o4e" PrP * tpe2, + 4e pre@ioul reporte" (P+r$!i &$ '!., 1997), 4!ere+, + eLpe$te" ?rom pre@ioureult ( ot+ri &$ '!., 200>; P+r$!i &$ '!., 2009-), mot $+e belon'in' to t!e M= 2por+"i$ -# ubtpe !o4e" + "uplet in$lu"in' + 20 #+ b+n" in +""ition to t!e 19 #+?r+'ment (i'. 2). !e onl +tpi$+l $+e 4+ MM +t $o"on 129 +n" !o4e" + protein+ereit+nt PrP* $ore o? +bout 20 #+, 4!i$! mi'r+te" li'!tl ?+ter t!+n tpi$+l tpe 1

(i'. 2).

i'ure 2











































































etern blot pro?ile o? PrP* eLtr+$te" ?rom !um+n br+in o? t!e H erie o?tr+nmitte" "ie+e (/ro4n &$ '!., 199>). A $+e ?or e+$! o? t!e "i??erent mole$ul+rubtpe t!+t 4ere ino$ul+te" in mone i !o4n (l+ne 1–6). 3+ne 2 !o4 t!e )))

!e "emo'r+p!i$ +n" $l+i?i$+tion o? t!e "i??erent !um+n * ub'roup, b+e" on t!e

mole$ul+r +n+le, +re !o4n in +ble 1. n +""ition to t!e uru $+e, t!e erie$omprie ot!er !itori$+ll rele@+nt $+e reporte" in t!e liter+ture be?ore t!e +"@ent o?mole$ul+r biolo' +n" t!e "i$o@er o? PrP* +n" PRNP . !e in$lu"e one $+e$l+i?ie" + +t+Li$ -# b /ro4nell +n" Eppen!eimer (1965), t!e +t+Li$ -# $+e"e$ribe" b Gomori &$ '!. (197%) +n" t!e +tpi$+l -# $+e, 4it! 4i"epre+" uru pl+Due, reporte" b *$!oene &$ '!. (1981). Mole$ul+r +n+le !o4e" t!+t bot! $+e4it! t!e +t+Li$ por+"i$ -# @+ri+nt 4ere ==2, 4!ere+ t!e $+e ?rom *$!oene &$ '!.(1981) 4+ 'enotpe" + MM +t $o"on 129 +n" $orrepon" to t!e +tpi$+l $+e"e$ribe" +bo@e 4it! t!e 20 #+ PrP* b+n" (i'. 2). !i p+tient !+" 4ore" + +neurour'eon ?or m+n e+r, 4!i$! r+ie t!e t!eoreti$+l poibilit t!+t !e !+" +ni+tro'eni$ ?orm o? -#, +lt!ou'! t!ere 4+ no re$or" o? !im p+rti$ip+tin' in +n oper+ti@e

pro$e"ure on + -# p+tient (*$!oene &$ '! . 1981).

+ble 1#emo'r+p!i$ $!+r+$teriti$ +n" $l+i?i$+tion o? tr+nmitte" $+e

Incubation times

n$ub+tion time in mone @+rie" i'ni?i$+ntl +mon' t!e "i??erent -# ub'roup(+ble 2).

+ble 2n$ub+tion time (in "+) in "i??erent mone pe$ie

ot+bl, in$ub+tion time in bot! Duirrel +n" pi"er mone 4ere !orter in +nim+lino$ul+te" 4it! tiue ?rom por+"i$ -# MM1 t!+n in t!oe ino$ul+te" 4it! por+"i$




http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947429/table/T1/






































i'ure 5P blot ?e+ture in Duirrel mone 4it! p!enotpe A (A) +n" / ((). (A) #i??ue

Wn+pti$X PrP t+inin' in t!e ?ront+l $orteL. (() ombine" n+pti$ +n" ?o$+l, pl+DueliePrP immunore+$ti@it in t!e "eep l+er o? t!e ?ront+l $orteL. )))

+ble %M+in ?e+ture o? p+t!olo'i$+l p!enotpe A +n" / in mone

n $ontr+t to p!enotpe A, pon'i?orm $!+n'e in p!enotpe / $onite" o? l+r'er@+$uole (i'. %), !o4e" + more $le+r$ut l+min+r p+ttern in t!e "eeper l+er o? t!e$erebr+l $orteL, +n" +??e$te" pre"omin+ntl ub$orti$+l tru$ture r+t!er t!+n t!e $erebr+l$orteL (i'. >, +ble %). mmuno!ito$!emitr +n" P blottin' re@e+le" ?o$+l,rel+ti@el m+ll, pl+Duelie PrP "epoit in +""ition to t!e n+pti$ t+inin' (i' % +n"+n"5 5).

!e +n+li o? + 'roup o? 18 +nim+l in 4!i$! -# or uru prion 4ere eri+lltr+nmitte" (i'. 1/) eit!er in Duirrel mone (2 "+ p++'e) or t!rou'! ot!er prim+te pe$ie u$! + $!imp+n<ee or pi"er mone be?ore t!e reine$tion in Duirrelmone (eri+l p++'e) +lo !o4e" t4o "itin$t p!enotpe $orrepon"in' to p!enotpe A +n" p!enotpe / b+e" on !itop+t!olo'i$+l +n" immuno!ito$!emi$+leL+min+tion o? t!e $erebr+l $orteL, 4!i$! 4+ +@+il+ble ?or +ll $+e.

!ther primate species

Alt!ou'! t!e m+teri+l +@+il+ble 4+ not u??i$ient ?or + "et+ile" $omp+rion o? leion pro?ile bet4een 'roup o? +nim+l re$ei@in' "i??erent ino$ul+, neurop+t!olo'i$+l?e+ture o? t!e "ie+e in $+pu$!in, pi"er +n" A?ri$+n 'reen mone 4ere $onitent4it! t!oe ober@e" in Duirrel mone.

n p+rti$ul+r, t4o p!enotpe repro"u$in' "itin$ti@e ?e+ture o? p!enotpe A +n" / in

Duirrel, u$! + @+$uole i<e, intr+$orti$+l "itribution o? pon'i?orm $!+n'e +n" t!e p+ttern o? PrP "epoition, 4ere een in bot! $+pu$!in +n" pi"er mone, 4!ere+ in t!em+ll 'roup o? A?ri$+n 'reen mone eL+mine" (4!i$! 4ere +ll ino$ul+te" 4it!por+"i$ -# MM1), +ll +nim+l !o4e" ?e+ture $onitent 4it! p!enotpe A.

(iochemical characteriation of PrPT&% in non-human primates






















omp+re" 4it! !um+n, t!e un'l$ol+te" prote+ereit+nt $ore o? PrP* in mone+l4+ mi'r+te" in t!e 20–21 #+ r+n'e +n" 4+ t!ere?ore ne@er $le+@e" $loe enou'! tot!e terminu to re+$! t!e lo4er rel+ti@e mole$ul+r m+ (i.e. 19 #+) o? !um+n PrP* tpe 2. n t!i re'+r" it i note4ort! t!+t, +t @+ri+n$e 4it! !um+n, +ll non!um+n prim+te pe$ie $+rr met!ionine +t $o"on 129 (er@enao@a &$ '!., 199>).

e@ert!ele, t4o i'ni?i$+ntl "i??erent mi'r+tion PrP* $ore pro?ile (!en$e?ort!re?erre" to + W+X +n" WbX) $oul" be "itin'ui!e" in bot! Duirrel (i'. 6) +n" $+pu$!inmone (i'. 7), p+rti$ul+rl 4!en lon' 'el 4it! in$re+e" reolution 4ere ue". !e?irt (more $ommon) pro?ile !o4e" +n un'l$ol+te" ?r+'ment o? t!e +me i<e + t!e!um+n PrP* tpe 1, 4!ere+ t!e e$on" pro?ile in$lu"e" + ?+ter mi'r+tin' ?r+'ment o?+bout 20 #+ in +""ition to t!e 21 #+ b+n" (i' 6 +n" +n"7). 7). Pro?ile W+X 4+ een in bot! Duirrel +n" $+pu$!in mone 4it! t!e p+t!olo'i$+l p!enotpe A, 4!ile pro?ile WbX4+ line" to p!enotpe / in t!ee t4o pe$ie. At @+ri+n$e 4it! Duirrel +n" $+pu$!inmone, t!e prote+ereit+nt PrP* $ore ?rom pi"er mone !+" + mole$ul+r i<e o?+bout 21 #+ (pro?ile W+X) in +ll +nim+l +n+le", irrepe$ti@e o? 4!et!er t!e !+" +

p+t!olo'i$+l p!enotpe A or /. in+ll, PrP

*

eLtr+$te" ?rom A?ri$+n 'reen mone,4!i$! 4+ eL+mine" onl in $+e 4it! p!enotpe A, +lo !o4e" + rel+ti@e mole$ul+rm+ o? 21∼ #+ $onitent 4it! pro?ile W+X.

i'ure 6mmunoblot +n+li o? prote+ereit+nt PrP* eLtr+$te" ?rom br+in o? Duirrelmone (l+ne %–10) ino$ul+te" 4it! "i??erent -# ubtpe or uru. /r+in!omo'en+te 4ere tre+te" 4it! protein+e +n" probe" 4it! %>. ApproLim+te

mole$ul+r )))

i'ure 7mmunoblot +n+li o? prote+ereit+nt PrP* eLtr+$te" ?rom br+in o? $+pu$!inmone (l+ne %–10) ino$ul+te" 4it! "i??erent -# ubtpe or uru. /r+in!omo'en+te 4ere tre+te" 4it! protein+e +n" probe" 4it! mono$lon+l +ntibo" 9A2.ApproLim+te )))

n +""ition to it i<e, t!e rel+ti@e +mount o? t!e t!ree m+or PrP* b+n" t!+t +re een+?ter immunoblottin' (t!e o$+lle" W'l$o?orm r+tioX) o?ten $!+r+$teri<e * ubtpeor prion tr+in. PrP* 'l$o?orm r+tio !o4e" + i'ni?i$+nt !etero'eneit in bot!Duirrel +n" pi"er mone. 4o PrP* pro?ile 4it! + t+titi$+ll i'ni?i$+nt "i??eren$ein 'l$o?orm r+tio 4ere ?oun" t!+t $orrel+te" 4it! p+t!olo'i$+l p!enotpe A +n" /,repe$ti@el, in bot! Duirrel +n" pi"er mone; in +""ition, in Duirrel mone, t!et4o 'l$op+ttern +lo m+t$!e" t!e t4o pro?ile W+X +n" WbX b+e" on PrP* i<e. !emore $ommon pro?ile 4+ $!+r+$teri<e" b t!e "omin+n$e o? t!e "i'l$ol+te" ?r+'mento? PrP* (or b imil+r +mount o? mono'l$ol+te" +n" "i'l$ol+te" PrP* ?orm in






















pi"er), 4!ere+ t!e e$on" pro?ile !o4e" + l+r'er +mount o? t!e mono'l$ol+te"?r+'ment (i'. 8). !e "i??eren$e bet4een t!e t4o PrP* 'l$o?orm p+ttern 4+epe$i+ll pronoun$e" in pi"er mone (i'. 8/). in+ll, in $+pu$!in mone, t!e'l$o?orm r+tio o? PrP* "i" not !o4 + i'ni?i$+nt "i??eren$e bet4een t!e mi'r+tion pro?ile W+X +n" WbX. Ho4e@er, +t @+ri+n$e 4it! Duirrel mone, t!e number o? $+e

+n+le", epe$i+ll ?or pro?ile WbX, 4+ @er lo4.

i'ure 8An+li o? PrP* 'l$o?orm r+tio in Duirrel (A) +n" pi"er (() mone ino$ul+te"4it! "i??erent -# ubtpe or uru. 4o "itin$t PrP* 'l$op+ttern, W"X +n" WmX +re!o4n. P+ttern W"X i $!+r+$teri<e" )))

e !+@e $+l$ul+te" t!e tot+l +mount o? PrP*

in e+$! br+in !omo'en+te obt+ine" ?romt!e Duirrel mone $erebr+l $orteL +n" ?oun" + i'ni?i$+nt @+ri+bilit +mon' t!e +??e$te"+nim+l, 4it!out +n i'ni?i$+nt $orrel+tion 4it! t!e "ie+e p!enotpe (i'. 9A). oe+r$! ?or poible "i??eren$e in ot!er bio$!emi$+l propertie u$! + t!e olubilit in"eter'ent, 4e !+@e +lo puri?ie" PrP* in + ele$te" 'roup o? Duirrel mone !o4in'eit!er PrP* mi'r+tion pro?ile W+X (n , 8) or pro?ile WbX (n , >) +n" e@+lu+te" t!e rel+ti@e proportion o? PrP* in t!e "eter'entoluble (*%) +n" inoluble (P%) ?r+$tion. !e+mount o? PrP* in t!e P% ?r+$tion 4+ @er imil+r bet4een t!e t4o 'roup, 4!ere+Duirrel +??e$te" b p!enotpe A !+" + i'ni?i$+ntl !i'!er +mount o? W"eter'ent olubleXPrP* $omp+re" 4it! t!oe 4it! p!enotpe / (i'. 9/).

i'ure 9(A) Amount o? protein+e reit+nt PrP* in Duirrel mone tot+l br+in !omo'en+te.!e t4o 'roup o? +nim+l !o4in' t!e PrP* pro?ile W+X (n , 56) or WbX (n , 16) on4etern blot +re )))

Pathological phenotypes: PrPT&% profiles and the type of human inocula

/ot! t!e p+t!olo'i$+l p!enotpe +n" PrP* pro?ile (eit!er t!e ele$trop!oreti$ mobilit ort!e 'l$op+ttern or bot!) in t!e mone 4ere i'ni?i$+ntl rel+te" to t!e tpe o? ino$ul+.!e "+t+ 4ere l+r'el $onitent +$ro +ll mone pe$ie, +lt!ou'! t!e "+t+ ?romDuirrel mone 4ere mu$! more in?orm+ti@e "ue to t!e !i'!er number o? +mple.!e "et+il $on$ernin' t!e $orrel+tion bet4een tpe o? ino$ulum, p+t!olo'i$+l

















p!enotpe +n" PrP* pro?ile, + 4ell + t!e number o? +nim+l +n+le" ?or e+$! 'roup,+re reporte" in +ble >. E@er+ll, +mple ?rom por+"i$ -# MM1 +n" M=1, i+tro'eni$-# MM1, por+"i$ -# MM1[2 +n" ?+mili+l -# $+rrin' t!e 200 mut+tion$ouple" 4it! met!ionine +t $o"on 129 pro"u$e" p!enotpe A +n" PrP* pro?ile W+X,4!ere+ t!e !omo'en+te ?rom por+"i$ -# ==2, por+"i$ -# M= 2 +n" ?rom t!e

uru $+e pro"u$e" p!enotpe / +n" PrP*

pro?ile WbX. L$eption to t!i rule 4erepi"er mone, 4!i$! !o4e" + PrP* prote+ereit+nt ?r+'ment $orrepon"in' to pro?ile W+X in +ll +nim+l +n+le", irrepe$ti@e o? 4!et!er t!e !+" + p+t!olo'i$+l p!enotpe A or /. e@ert!ele, t!e $orrel+tion bet4een t!e PrP* 'l$op+ttern +n" t!e p+t!olo'i$+l p!enotpe A +n" / in pi"er mone 4+ triin' (i'. 8, +ble >). A inDuirrel mone, t!e mot $ommon 'l$o?orm pro?ile 4+ ober@e" in +nim+l 4it! p+t!olo'i$+l p!enotpe A, 4!ile t!e e$on" pro?ile, $!+r+$teri<e" b + "omin+ntmono'l$ol+te" ?orm +n" + triin' un"errepreent+tion o? t!e "i'l$ol+te" ?orm,4+ line" to p!enotpe /.

+ble >P+t!olo'i$+l p!enotpe (P+t!) +n" PrP* mi'r+tion p+ttern in "i??erent mone pe$ie+$$or"in' to !um+n ino$ulum

in+ll, + in'le por+"i$ -# MM 2, in 4!i$! onl PrP* tpe 2 4+ "emontr+te" in

t4o +mple ?rom t!e $erebr+l $orteL +n" $erebellum, +lo !o4e" p!enotpe A +n"PrP* pro?ile W+X, 4!ere+ t!e +tpi$+l MM $+e 4it! t!e 20 #+ PrP* $ore !o4e" p!enotpe / +n" PrP* pro?ile WbX.

Go to:

"iscussion

n t!e preent tu" 4e !+@e $omp+re" t!e tr+nmiion propertie o? t!e mot $ommon p!enotpi$ ubtpe o? por+"i$, ?+mili+l +n" i+tro'eni$ -# + 4ell + uru in "i??erent

non!um+n prim+te pe$ie. !i erie o? tr+nmitte" $+e i !itori$+ll uniDue, + it i b+e" on t!e l+r'e H tu" t!+t pro@i"e" t!e eenti+l e@i"en$e t!+t !um+n * +retr+nmiible.

!e tr+nmiion "+t+ in prim+te tron'l u''et t!+t t4o "itin$t prion tr+in +reline" to t!e t!ree mot $ommon por+"i$ -# @+ri+nt, 4!i$! +$$ount ?or t!e 're+tm+orit o? !um+n prion "ie+e. More pe$i?i$+ll, our reult !o4 t!+t t!e mo$loni$-# p!enotpe +o$i+te" 4it! PrP* tpe 1 in $o"on 129 MM or M= PRNP 'enotpe














(P+r$!i &$ '!., 1999) i rel+te" to + prion tr+in t!+t i "itin$t ?rom t!+t +o$i+te" 4it!t!e +t+Li$ +n" t!e urupl+Due p!enotpe line" to PrP* tpe 2 +n" == or M=,repe$ti@el (P+r$!i &$ '!., 1999).

!e reult o? t!i tu" +lo !o4 t!+t uru prion !+@e tr+nmiion propertie

eDui@+lent to por+"i$ -# ==2 +n" M=2 4it! uru pl+Due (M= 2). !e ?in"in' i inline 4it! pre@iou reult un"erlin' t!e triin' imil+ritie in bot! $lini$op+t!olo'i$+l?e+ture +n" PrP* propertie bet4een por+"i$ -# ==2 or M= 2 +n" uru(H+in?ellner &$ '!., 1997; P+r$!i &$ '!., 1997; M$3e+n &$ '!., 1998; /r+n"ner &$ '!., 2008;M$3e+n, 2008). E@er+ll, t!e ?in"in' $on?irm t!e i"e+ t!+t uru ori'in+te" ?rom t!e$!+n$e $onumption +n" $+nnib+liti$ "i??uion o? tiue ?rom +n in"i@i"u+l 4it!por+"i$ -#, +n" point to t!e prob+bilit o? eit!er + ==2 or +n M= 2 $+e, in$e 4e"i" not ?in" e@i"en$e o? por+"i$ -# MM1 prion in eLperiment+ll tr+nmitte" uru,e@en in ube$t $+rrin' t!e MM or M= 'enotpe. nteretin'l, re$entl per?orme"Wtr+$e b+$X eLperiment !+@e in"i$+te" t!+t tr+nmiion o? por+"i$ -# ==2 to + 129MM in"i@i"u+l t!rou'! + "ur+ impl+nt 4+ +lo t!e me$!+nim 'ener+tin' t!e i+tro'eni$

-# p!enotpe +o$i+te" 4it! pl+Due, $+lle" p"-# (ob++!i &$ '!., 2010). !ee?in"in' +re $onitent 4it! our ober@+tion in t!e uru $+e 4it! MM 'enotpe +n" int!e +tpi$+l MM $+e 4it! uru pl+Due +n" t!e PrP* 20 #+ b+n". !u, it +ppe+r t!+tt!i prion tr+in, +lt!ou'! more ?reDuentl +o$i+te" 4it! t!e = $o"on 129 +llele, +lotr+nmit to in"i@i"u+l !omo<'ou ?or t!e $o"on 129 met!ionine +llele, in 4!i$! it imole$ul+rl +n" p!enotpi$+ll "itin'ui!+ble ?rom t!e mot $ommon MM&M=1+o$i+te" tr+in. E? note, i+tro'eni$ -# rel+te" to $ont+min+te" 'ro4t! !ormoneine$tion i +lo $!+r+$teri<e" b +mloi" pl+Due "epoition o? uru tpe +n" +lo +??e$tt!e MM 'enotpe in +""ition to 129 == +n" M= re$ipient (/illette "e =illemeur, 199>;ill, 200%; /ro4n, 2006).

!e "i??erent tr+nmiion propertie o? por+"i$ -# tpe 1 ino$ul+ in MM or M=$o"on 129 'enotpe $omp+re" 4it! t!e tpe 2 ino$ul+ in == or M= 'enotpe +re +lo$onitent 4it! "+t+ re$entl obt+ine" in tr+n'eni$ mi$e +n" "n ."$ro mo"el. !e tu"ie$on"u$te" in tr+n'eni$ mi$e eLprein' eit!er !um+n MM, == or M= 'enotpe +re o? p+rti$ul+r interet ?or + $omp+rion 4it! our reult, +lt!ou'! mot o? t!em !+@e ?o$ue"on @+ri+nt -# +n", to + leer eLtent, on 'eneti$ *, 4!ere+ t!e "+t+ $olle$te" t!u?+r $on$ernin' t!e por+"i$ -# ubtpe +n" uru +re p+t$! +n" in$on$lui@e. *por+"i$-# prion tr+nmitte" to tr+n'eni$ mi$e 4it! eit!er MM or == 'enotpe, 4it!in$ub+tion time t!+t +re $onitent 4it! our $on$luion t!+t t!e MM1&M=1 +n"==2&M= 2 por+"i$ -# ubtpe +re line" to t4o "i??erent !um+n prion tr+in(ort! &$ '!., 200%). *imil+r "+t+ on in$ub+tion time 4ere obt+ine" in +not!er tu"4!ere + ?e4 por+"i$ -# ino$ul+ 4ere tr+nmitte" to tr+n'eni$ mi$e eLprein' !um+nPrP 4it! M +t $o"on 129 to be $omp+re" 4it! t!e tr+nmiion propertie o? bo@inepon'i?orm en$ep!+lop+t! +n" @+ri+nt -# prion (A+nte &$ '!., 2002).

!e inter+$tion bet4een !ot 'enotpe o? t!e Wubtr+teX +n" t!e 'enotpe +n" PrPio?orm o? t!e prion Wee"X !+@e +lo been re$entl mo"elle" "n ."$ro uin' t!e proteinmi?ol"in' $$li$+l +mpli?i$+tion (PMA) te$!niDue. t !+ been ?oun" t!+t ee" ?romM=1 +mpli?ie" e??i$ientl in MM (+n" to + leer "e'ree M=) ubtr+te +n" t!ere?ore















































be!+@e imil+rl to MM1, 4!ere+ M=2, imil+rl to ==2, +mpli?ie" e??i$ientl in ==ubtr+te (-one &$ '!., 2008), 4!i$! i +lo $onitent 4it! t!e reult o? t!e preenttu".

!e tr+nmiion propertie o? uru +n" -# iol+te !+@e +lo been $omp+re" in

tr+n'eni$ +n" 4il"tpe mi$e. +"4ort! &$ '!. (2008) in?erre" t!+t uru prion +re"itin$t ?rom @+ri+nt -# +n" !+@e tr+nmiion propertie eDui@+lent to t!oe o?$l+i$+l (por+"i$) -# prion, 4!ere+ M+nueli"i &$ '!. (2009) +r'ue" t!+t t!e uru+'ent i + uniDue iol+te "itin$t ?rom -#. n?ortun+tel, t!e ?+$t t!+t +"4ort! &$ '!.(2008) ?+ile" to ?ull $!+r+$teri<e t!e !etero'eneit +o$i+te" 4it! por+"i$ -# prion+?ter tr+nmiion, +n" M+nueli"i &$ '!. (2009) "i" not mention 4!i$! iol+te o? por+"i$-# (i.e. mole$ul+r&p+t!olo'i$+l ubtpe) 4+ ue" ?or tr+nmiion, limit t!einterpret+tion o? t!eir reult +n" t!e $omp+rion 4it! t!e preent tu". e@ert!ele, 4e4oul" +'ree 4it! t!e 'ener+l $on$luion o? +"4ort! &$ '!. (2008) but +lo !o4 t!+turu prion "o not m+t$! t!e entire pe$trum o? por+"i$ -#.

An in$re+in' bo" o? "+t+ in"i$+te t!e eLiten$e o? -# $+e 4it! PrP

*

tpe 1 +n" 2$oo$$urren$e in t!e +me br+in (P+r$!i &$ '!., 1999; Puoti &$ '!., 1999). e re$entl?oun" t!+t in por+"i$ -# t!e $oo$$urren$e o? PrP* tpe 1 +n" 2 in@ol@e +bout %5Uo? por+"i$ -# $+e +n" epe$i+ll +??e$t ube$t 4it! + $o"on 129 MM 'enotpe(+lc &$ '!., 2009; P+r$!i &$ '!., 2009-). n t!e preent erie o? tr+nmitte" $+e, t!e per$ent+'e o? MM $+e 4it! t!e $oo$$urren$e o? PrP* tpe 1 +n" 2 4+ i'ni?i$+ntllo4er, 4!i$! i $onitent 4it! t!e l+$ o? u??i$ient tiue to per?orm re'ion+l +n+le. e@ert!ele, it i note4ort! t!+t +p+rt ?rom t!e +tpi$+l MM $+e 4it! t!e uru pl+Due+n" t!e 20 #+ b+n" +n" t!e MM uru $+e, +ll MM $+e 4it! ?e+ture o? t!e MM 2por+"i$ -# ubtpe !o4e" i"enti$+l tr+nmiion propertie in"epen"ent o? t!e preen$e o? PrP* tpe 2 +n" it rel+ti@e +mount. !i +lo in$lu"e" one $+e in 4!i$!

4e 4ere +ble to "ete$t onl PrP

*

tpe 2 in t!e t4o +mple t!+t 4ere +@+il+ble. !ere+re t4o poible eLpl+n+tion ?or t!ee reult. Potenti+ll, t!e prim+te pe$ie ue" 4eremu$! more u$eptible to MM1 t!+n MM 2 prion +n" t!i pre@ente" t!e +ppe+r+n$e o? !itop+t!olo'i$+l ?e+ture rel+te" to MM 2 repli$+tion. Altern+ti@el, t!e MM 2 p!enotpe in !um+n i not rel+te" to + pe$i?i$ prion tr+in but r+t!er to !ot 'enotpi$?+$tor t!+t +re reponible ?or t!e ($o)+ppe+r+n$e o? tpe 2 +n" t!e +o$i+te" MM 2 p!enotpe. urt!er tr+nmiion tu"ie uin' +nim+l t!+t +re le permii@e to -#MM&M= 1 or -# ==2 prion 4ill be nee"e" to "e?initi@el ol@e t!i iue.

!e preent "+t+ +lo !+@e impli$+tion ?or t!e un"ert+n"in' o? ?+mili+l +n" +$Duire"?orm o? prion "ie+e. e pre@ioul !o4e" t!+t tpe 1 +n" tpe 2 PrP* +re preentin +ll ?orm o? -# in"epen"ent o? t!e +pp+rent +etiolo' o? t!e "ie+e, i.e. por+"i$,in!erite" or +$Duire" b in?e$tion (P+r$!i &$ '!., 1997, 2000). !ee ober@+tion r+ie t!e$riti$+l Duetion o? 4!et!er t!e +me b+i$ tr+in preent in por+"i$ -# +re +lo+o$i+te" 4it! t!e ?+mili+l ?orm o? t!e !um+n "ie+e +n", i? t!i i t!e $+e, 4!et!ert!e uniDue p!enotpi$ ?e+ture o? ome ?+mili+l prion "ie+e $+n be eLpl+ine" b +ne??e$t o? t!e PRNP mut+tion t!+t i in"epen"ent ?rom t!e prion tr+in.






















































!e preent "+t+ on t!e tr+nmiion o? i+tro'eni$ -# +n" ?+mili+l -# to prim+te+lon' 4it! reult o? tr+nmiion eLperiment o? ?+mili+l -# prion (200129 M +n"210=129 M !+plotpe) in b+n @ole ( onno &$ '!., 2005) +n" ?+mili+l -# (200129 M +n" 200129=) in tr+n'eni$ !um+ni<e" mi$e (A+nte &$ '!., 2009) +re$onitent 4it! t!i !pot!ei. nteretin'l, in t!e l+tter tu" it 4+ ?oun" t!+t +t

@+ri+n$e 4it! t!e 200129MM ino$ulum, t!e 200129== ino$ulum tr+nmitte"4it! + prolon'e" in$ub+tion time +n" t!e +??e$te" mi$e !o4e" pl+Duelie ?o$+l"epoit, 4!i$! p+r+llel our ?in"in' 4it! por+"i$ -# MM1 +n" ==2 prion in non!um+n prim+te.

Pre@iou tu"ie on por+"i$ -# MM1, t!e mot $ommon por+"i$ !um+n -# ubtpe,!+@e r+ie" t!e Duetion o? 4!et!er t!i rel+ti@el l+r'e 'roup o? $+e i !omo'eneou+n" rel+te" to + in'le prion tr+in or r+t!er repreent + !etero'eneou 'roup in$lu"in't4o or more por+"i$ -# ubtpe. !e preent tu", b+e" on t!e l+r'et 'roup o?tr+nmitte" por+"i$ -# MM1 $+e to "+te, !o4e" !omo'eneou reult in term o?in$ub+tion time, tpe o? pon'i?orm $!+n'e, leion pro?ile +n" PrP* propertie. !e

$olle$ti@e reult, t!ere?ore, tron'l upport t!e i"e+ t!+t + in'le prion tr+in i+o$i+te" 4it! por+"i$ -# MM1, +n" +re in eepin' 4it! our ori'in+l $l+i?i$+tion, +t@+ri+n$e 4it! ot!er $l+i?i$+tion tem t!+t $oni"ere" our MM1 $+e + +!etero'eneou 'roup in$lu"in' t4o tr+inrel+te" ubtpe (+nuo &$ '!., 2001; Hill &$

'!., 200%).

or m+n e+r it !+ been "eb+te" 4!et!er t!e tu" o? ?r+'ment i<e +n" 'l$o?ormr+tio o? PrP* pro@i"e u??i$ientl "itin$ti@e mole$ul+r m+rer to +llo4 i"enti?i$+tiono? prion tr+in. Eur "+t+ in"i$+te t!+t in !um+n, t!e PrP* pro?ile pro@i"e i'ni?i$+ntin?orm+tion +bout t!e $+u+ti@e tr+in, +lt!ou'! it i not in"i$+ti@e o? it un"er +ll$ir$umt+n$e in t!e +ben$e o? !itop+t!olo'i$+l "+t+. or eL+mple, it i till "i??i$ult to

"itin'ui! bet4een $+e 4it! t!e +me PrP

*

tpe (?or eL+mple, bet4een MM 2 +n"MM 2) 4it!out no4in' t!e !itop+t!olo'i$+l "+t+. urt!ermore, re$ent 4or ?rom our'roup !+ !o4n t!+t in ome int+n$e t!e !itop+t!olo'i$+l eL+min+tion i e@en moreeniti@e t!+n t!e bio$!emi$+l PrP* tpin' in t!e re$o'nition o? por+"i$ -# $+e4it! miLe" p!enotpi$ ?e+ture (P+r$!i &$ '!., 2009-).

on$ernin' t!e @+lue o? PrP* tpin' in t!e re$o'nition o? tr+in +??e$tin' "i??erentpe$ie, it !+ been pre@ioul !o4n t!+t bot! PrP* i<e +n" 'l$o?orm p+ttern m+$!+n'e +?ter interpe$ie tr+nmiion (Hill &$ '!., 1997; ob++!i &$ '!., 2010). n+'reement 4it! t!i @ie4, tr+nmiion o? por+"i$ -# MM&M= 1 to non!um+n prim+te $onitentl repro"u$e" t!e i<e but not t!e 'l$o?orm r+tio o? t!e ori'in+l tpe.@en more triin'l, tr+nmiion o? por+"i$ -# ==2 or M= 2 "i" not repro"u$et!e i<e in bot! pi"er +n" Duirrel mone, +n" t!e 'l$o?orm r+tio in pi"er mone.n t!i re'+r" it i note4ort! t!+t, +t @+ri+n$e 4it! por+"i$ -# ==2 or M= 2+??e$te" ube$t, bot! pi"er +n" Duirrel mone +re !omo<'ou ?or met!ionine +t$o"on 129 (er@enao@a &$ '!., 199>). !ere?ore, our "+t+ $on?irm t!+t PrP* tpin' pro@i"e + mole$ul+r i'n+ture ?or $ert+in prion tr+in 4it!in + $ert+in !ot 'enotpe, p+rti$ul+rl 4!en $ombine" 4it! 'eneti$ +n" neurop+t!olo'i$+l "+t+, but i o? limite"





































@+lue ?or tr+$in' t!eir p++'e +mon' "i??erent +nim+l pe$ie 4it!out tr+nmiioneLperiment.

E@er+ll, t!e reult o? t!i tu", $ombine" 4it! t!oe obt+ine" b ot!er 'roup, in"i$+tet!+t +t le+t ?our "itin$t tr+in o? prion +??e$t !um+n. A$$or"in' to t!eir rel+ti@e

?reDuen$ in 4etern $ountrie t!e 4oul" in$lu"e: (i) *tr+in A, rel+te" to t!e tpi$+l -# p!enotpe or mo$loni$ @+ri+nt (PrP* tpe 1 +n" +t le+t one M $o"on 129 +llele); (ii)*tr+in /, rel+te" to t!e +t+Li$ +n" urupl+Due @+ri+nt o? -# + 4ell + uru (PrP* tpe 2 +n" +t le+t one = $o"on 129 +llele or PrP* o? 20 #+ in $ombin+tion 4it! $o"on129 MM); (iii) *tr+in , rel+te" to @+ri+nt -# (PrP* tpe 2/ +n" +t le+t one M $o"on129 +llele); +n" (i@) *tr+in #, rel+te" to ?+t+l inomni+, 4it! PrP* tpe 2A (por+"i$?orm) or 2/ (?+mili+l ?orm) +n" +t le+t one M $o"on 129 +llele.

!et!er +""ition+l !um+n prion tr+in +re rel+te" to por+"i$ -# MM 2, por+"i$-# ==1, t!e re$entl i"enti?ie" +tpi$+l por+"i$ * $+e (G+mbetti &$ '!+ , 2008) orome r+re 'eneti$ ?orm o? + et untr+nmitte" prion "ie+e rem+in to be "etermine".

Go to:

3unding

E (i$er$+ on"+ment+le Erient+t+) ?rom t!e ni@erit o? /olo'n+ +n" t!e GinoG+lletti oun"+tion (to P.P.), +tion+l ntitute o? He+lt! 'r+nt PH* AG0101%% +n" P01AG1>%59.

Go to:

Acknowledgements

!e +ut!or +re t!+n?ul to #i+ne o?e, /+rb+r+ Poli$!i, oe i$!+r"on +n"*+brin+ /onine'n+ ?or t!eir te$!ni$+l +it+n$e. !e +ut!or +re +lo 'r+te?ul to #rGi+nlui'i +nuo ?or !i !elp in t!e $olle$tion o? tiue.

Go to:

Glossary

Abbre7iations

-#reut<?el"t–-+ob "ie+e

H +tion+l ntitute o? He+lt!

*tr+nmiible pon'i?orm en$ep!+lop+t!ie














Go to:

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57. P+r$!i P, Giee A, +pell+ri *, /ro4n P, *$!ul<*$!+e??er , in"l E, et +l.l+i?i$+tion o? por+"i$ reut<?el"t-+ob "ie+e b+e" on mole$ul+r +n" p!enotpi$ +n+li o? %00 ube$t. Ann eurol. 1999;>6:22>–%%. IPubMe"J

58. P+r$!i P, ot+ri *, eber P, *$!immel H, /u"+ H, errer , et +l. nterl+bor+tor +ement o? PrP* tpin' in reut<?el"t-+ob "ie+e: + 4etern











































blot tu" 4it!in t!e euroPrion onortium. /r+in P+t!. 2009+;19:%8>–91.IPubMe"J

59. P+r$!i P, *tr+mmiello , ot+ri *, Giee A, 3+n'e@el" -, 3+"o'+n+ A, et +l.n$i"en$e +n" pe$trum o? por+"i$ reut<?el"t-+ob "ie+e @+ri+nt 4it! miLe" p!enotpe +n" $oo$$urren$e o? PrP* tpe: +n up"+te" $l+i?i$+tion. A$t+

europ+t!. 2009b;118:659–671. IPM ?ree +rti$leJ IPubMe"J60. P+r$!i P, ou , +n' , /ro4n P, +pell+ri *, G!etti /, et +l. Geneti$ in?luen$eon t!e tru$tur+l @+ri+tion o? t!e +bnorm+l prion protein. Pro$ +tl A$+" *$i*A. 2000;97:10168–72. IPM ?ree +rti$leJ IPubMe"J

61. Pruiner */. Prion. Pro$ +tl A$+" *$i *A. 1998;95:1%%6%–8%. IPM ?ree+rti$leJ IPubMe"J

62. Puoti G, Gi+$$one G, oi G, +n$i+ni /, /u'i+ni E, +'li+@ini . *por+"i$reut<?el"t-+ob "ie+e: $oo$$urren$e o? "i??erent tpe o? PrP* in t!e +me br+in. eurolo'. 1999;5%:217%–6. IPubMe"J

6%. obert G, 3o?t!oue , /ro4n , ro4 -, /+rr A, Pruiner */. Prion protein immunore+$ti@it in !um+n tr+nmiible "ementi+. n'l - Me".

1986;%150:12%1–%. IPubMe"J6>. *+?+r -, ille H, tri =, Grot! #, *erb+n H, or$!i+ M, et +l. i'!t prion tr+in!+@e PrP* mole$ule 4it! "i??erent $on?orm+tion. +t Me". 1998;>:1157–65.IPubMe"J

65. *$!oene , M+ter 3, Gibb -, G+"ue #, ler H, Moore #, et +l.r+nmiible pon'i?orm en$ep!+lop+t! (reut<?el"t-+ob "ie+e). Atpi$+l$lini$+l +n" p+t!olo'i$+l ?in"in'. Ar$! eurol. 1981;%8:>7%–7. IPubMe"J

66. *$!ul<*$!+e??er -, $!fe *, r+ne?u , #rfe , H+ueeitner #, GieeA, et +l. !e p+r+??inembe""e" tiue blot "ete$t PrP* e+rl in t!e in$ub+tiontime in prion "ie+e. Am - P+t!ol. 2000;156:51–6. IPM ?ree +rti$leJ IPubMe"J

67. *$rim'eour M, M+ter 3, Alper MP, +@en -, G+"ue #. A $lini$o p+t!olo'i$+l tu" o? + $+e o? uru. - eurol *$i. 198%;59:265–75. IPubMe"J

68. *omer@ille A, !on' A, MulDueen E, /irett , oo" *, Hope -./io$!emi$+l tpin' o? $r+pie tr+in. +ture. 1997;%86:56>. IPubMe"J

69. ellin' G, P+r$!i P, #eArmon" *-, ortelli P, Mont+'n+ P, G+bi<on , et +l.@i"en$e ?or t!e $on?orm+tion o? t!e p+t!olo'i$ io?orm o? t!e prion proteinen$ip!erin' +n" prop+'+tin' prion "i@erit. *$ien$e. 1996;27>:2079–82.IPubMe"J

70. +"4ort! -#, -oiner *, 3ine!+n -M, #ebrul+i M, oL , ooper *, et +l.uru prion +n" por+"i$ reut<?el"t-+ob "ie+e prion !+@e eDui@+lenttr+nmiion propertie in tr+n'eni$ +n" 4il"tpe mi$e. Pro$ +tl A$+" *$i*A. 2008;105:%885–90. IPM ?ree +rti$leJ IPubMe"J

71. em!euer M, /enet+" *3, re"e A, *$!ul<e*turm , em!euer ,H+!m+nn , et +l. *imil+ritie bet4een ?orm o? !eep $r+pie +n" reut<?el"t-+ob #ie+e +re en$o"e" b "itin$t prion tpe. Am - P+t!ol. 2009;175:2566– 7%. IPM ?ree +rti$leJ IPubMe"J

72. eim+nn . !e t+te o? t!e prion. +t e@ Mi$robiol. 200>;2:861–71.IPubMe"J

7%. ill G. A$Duire" prion "ie+e: i+tro'eni$ -#, @+ri+nt -#, uru. /r Me"/ull. 200%;66:255–65. IPubMe"J

















































7>. +nuo G, +rin+<<o A, iorini M, Gel+ti M, +t+'n+ A, i'!etti PG, et +l. pH"epen"ent prion protein $on?orm+tion in $l+i$+l reut<?el"t-+ob "ie+e. -/iol !em. 2001;276:>0%77–80. IPubMe"J

75. ou O, 3+n'e@el" -, î+o ^, !en *, M$Geer P3, Yu+n -, et +l. PrP$on?orm+tion+l tr+nition +lter pe$iepre?eren$e o? + PrP pe$i?i$ +ntibo". -

/iol !em. 2010;285:1%87>–8>. IPM ?ree +rti$leJ IPubMe"J

Jurnal ;=irol -. 2011; 8: 559.Publi!e" online 2011 #e$ember 2>. "oi: 10.1186&17>%>22^8559PM#: PM%296552

An o7er7iew of human prion diseases

Mu!+mm+" mr+n1 +n" *+Dib M+!moo" 2


Abstract

Prion "ie+e +re tr+nmiible, pro'rei@e +n" in@+ri+bl ?+t+l neuro"e'ener+ti@e$on"ition +o$i+te" 4it! mi?ol"in' +n" +''re'+tion o? + !oten$o"e" $ellul+r prion protein, PrP. !e !+@e o$$urre" in + 4i"e r+n'e o? m+mm+li+n pe$ie in$lu"in'!um+n. Hum+n prion "ie+e $+n +rie por+"i$+ll, be !ere"it+r or be +$Duire".*por+"i$ !um+n prion "ie+e in$lu"e ruet<?el"t-+$ob "ie+e (-#), ?+t+l inomni++n" @+ri+bl prote+eeniti@e prionop+t!. Geneti$ or ?+mili+l prion "ie+e +re $+ue" b +utoom+l "omin+ntl in!erite" mut+tion in t!e 'ene en$o"in' ?or PrP +n" in$lu"e?+mili+l or 'eneti$ -#, ?+t+l ?+mili+l inomni+ +n" Gertm+nn*trùler*$!einern"rome. A$Duire" !um+n prion "ie+e +$$ount ?or onl 5U o? $+e o? !um+n prion"ie+e. !e in$lu"e uru, i+tro'eni$ -# +n" + ne4 @+ri+nt ?orm o? -# t!+t 4+tr+nmitte" to !um+n ?rom +??e$te" $+ttle @i+ me+t $onumption epe$i+ll br+in. !ire@ie4 preent in?orm+tion on t!e epi"emiolo', etiolo', $lini$+l +ement,neurop+t!olo' +n" publi$ !e+lt! $on$ern o? !um+n prion "ie+e. !e role o? t!e PrPen$o"in' 'ene ( PRNP ) in $on?errin' u$eptibilit to !um+n prion "ie+e i +lo"i$ue".

/eywords4 Prion, Prion "ie+e, PRNP , *, -#Go to:

(ackground




http://dx.doi.org/10.1186%2F1743-422X-8-559

http://www.ncbi.nlm.nih.gov/pubmed/?term=Imran%20M%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Mahmood%20S%5Bauth%5D













http://dx.doi.org/10.1186%2F1743-422X-8-559

http://www.ncbi.nlm.nih.gov/pubmed/?term=Imran%20M%5Bauth%5D










Prion "ie+e +re tr+nmiible protein mi?ol"in' "ior"er in 4!i$! mi?ol"in' o? +!oten$o"e" prion protein (PrP) o$$ur. PrP i + 25% +mino +$i" (++) protein. !e ?irt22 termin+l ++ +re remo@e" ?rom PrP +?ter it tr+nport to en"opl+mi$ reti$ulum,4!ile t!e l+t 2% termin+l ++ +re $le+@e" o?? +?ter t!e +""ition o?'l$olp!op!+ti"linoitol (GP) +n$!or, 4!i$! !elp t!e protein to +tt+$! to t!e outer

ur?+$e o? $ell membr+ne. PrP m+ eLit in t4o ?orm: + norm+l $ellul+r prion protein"ei'n+te" + PrP +n" + p+t!o'eni$ mi?ol"e" $on?ormer "ei'n+te" + PrP*$. /ot! PrP

+n" PrP*$ $on?ormer +re en$o"e" ?rom t!e +me eDuen$e o? t!e 16 b in'le $op PRNP 'ene t!+t i poitione" on t!e !ort (p) +rm o? !um+n $!romoome 20 (20p1%),?rom b+e p+ir >,666,796>,682,2%%. !e !um+n PRNP $ont+in t4o eLon 4it! t!ee$on" one $+rrin' t!e 4!ole open re+"in' ?r+me. !e +bnorm+l PrP*$ io?orm "i??er?rom t!e norm+l PrP io?orm in e$on"+r +n" terti+r tru$ture, but not in prim+r+mino +$i" eDuen$e. PrP i pre"omin+ntl ri$! in +lp!+ !eli$+l $ontent, 4!ile PrP*$ i pre"omin+ntl ri$! in bet+ !eet $ontent I15J. !i $on?orm+tion+l "i$rep+n$ ren"ert!e PrP*$ io?orm eLtremel reit+nt to proteoli +n" "e'r+"+tion b $on@ention+lme+n o? $!emi$+l +n" p!i$+l "e$ont+min+tion or "iin?e$tion. n $ontr+t to PrP*$,

PrP

i oluble in non"en+turin' "eter'ent +n" i $ompletel "e'r+"e" b prote+eI1,%J.

!e uper$ript (*$) !+ been ue" to re?er to $r+pie, t!e ?irt +n" t!e mot +n$ient+nim+l r+nmiible *pon'i?orm n$ep!+lop+t! (*). M+n +ut!or +lo ueuper$ript ot!er t!+n (*$) to "itin'ui! norm+l +n" p+t!o'eni$ ("ie+e$+uin')io?orm. !ee in$lu"e (re) ?or reit+nt +n" (#i) ?or "ie+e. An +bbre@i+te" n+me o? + prion "ie+e $+n +lo be ue" + uper$ript to point out t!e ori'in o? t!e p+t!o'eni$io?orm i.e. PrP*$ or PrP-#. !e p+t!o'eni$ $on?ormer +re impl $+lle" prion (t!ein?e$tiou protein p+rti$le) I%J.

A$$or"in' to ee"in'nu$le+tion mo"el, t!e preeLitin' or +$Duire" PrP

*$

oli'omer$+t+l<e t!e $on@erion o? PrP mole$ule into PrP*$ ?ibril t!e bre++'e o? 4!i$! pro@i"e more PrP*$ templ+te ?or t!e $on@erion pro$e. !e pro$e o? prion prop+'+tion in t!e br+in reult in t!e p+t!o'enei o? prion "ie+e I6J. *iLteen "i??erent@+ri+nt o? prion "ie+e !+@e been reporte" o ?+r: nine in !um+n +n" e@en in +nim+l.!e etiolo', !ot r+n'e +n" e+r o? "e$ription ?or t!ee "ie+e @+ri+nt +re 'i@en in+ble +ble1. 1. n t!e preent re@ie4, + brie? "e$ription o? !um+n prion "ie+e i pro@i"e".

+ble 1tiolo' o? prion "ie+e
























!e $lini$op+t!olo'i$+l +n" mole$ul+r p!enotpe o? -# +re 're+tl in?luen$e" b@+ri+tion in PRNP . PRNP polmorp!im in re'ul+tor + 4ell + $o"in' eDuen$e!+@e been +o$i+te" 4it! pre"ipoition to t!e "ie+e "e@elopment I%>%6J.Homo<'oit +t M129= polmorp!im i + tron' ri ?+$tor ?or t!e "e@elopment o?-# I%6,%7J. n -+p+nee, !omo<'oit +t +not!er PRNP polmorp!im 219 i +lo

+ ri ?+$tor ?or t!e "e@elopment o? -# I%8,%9J. 219 !+ been ?oun" in onl Ai+n+n" P+$i?i$ popul+tion 4!i$! +re more !omo<'ou ?or met!ionone +t $o"on 129 +$omp+re" to etern popul+tion I27,>0J. ne??i$ient inter+$tion bet4een !eterolo'ouPrP mole$ule en$o"e" ?rom "itin$t PRNP +llele (129 M +n" 129 =) m+ retri$t t!e$on@erion o? PrP into PrP*$. An $ontr+int in t!e pro$e o? prion prop+'+tion i+ume" to lo4 "o4n t!e pro'reion o? t!e "ie+e I%6J. !e $lini$+l p!enotpi$!etero'eneit een in -# $+e $+n be +ttribute" to "i??erent prion tr+in. A tr+in i bio$!emi$+ll "e?ine" b p+ttern +n" r+tio o? PrP*$ ?r+'ment on etern blot. !reeM129= 'enotpe (129 MM, 129 M= +n" 129 ==) +n" 2 tr+in tpe (tpe 1 +n" tpe 2)$+n be $ouple" into 6 $ombin+tion (MM1, M=1, ==1, MM2, M=2 +n" ==2) 4!i$!$orrepon" @er 4ell to "i??erent $lini$+l p!enotpe o? -#. En t!e b+i o? t!ee 6

$ombin+tion, t!ree "i??erent tr+in $l+i?i$+tion tem !+@e been propoe" I%2,>1>%J.

3atal familial insomnia <33I=

Pre@ioul no4n + t!+l+mi$ "ementi+ but ren+me" in 1986 + ?+t+l ?+mili+l inomni+() i +n +utoom+l "omin+ntl in!erite" !um+n prion "ie+e. i $+ue" b + PRNP mut+tion #178 line" to met!ionine o? t!e PRNP polmorp!im M129=. !enline" to @+line +t t!e $o"on 129, t!e +me mut+tion le+" to + "i@ere p!enotpe o??&'-# I2%,>>,>5J. *o ?+r, +lmot 100 $+e o? in +lmot >0 ?+milie !+@e beenreporte" ?rom t+l, Germ+n, Autri+, *p+in, , r+n$e, inl+n", t!e nite" *t+te,Autr+li+, -+p+n, !in+, +n" Moro$$o I>6J.

o$$ur eDu+ll in men +n" 4omen 4it!out +n i'ni?i$+nt "i??eren$e bet4een 129MM +n" 129 M= 'enotpe. Ho4e@er, t!e "ie+e "ur+tion m+ be i'ni?i$+ntl !orterin 129 MM ube$t. !e $+e preent bet4een 20 +n" 72 e+r 4it! +n +@er+'e o?>9 e+r +n" m+ li@e +?ter t!e "ie+e onet ?or 872 mont! 4it! +n +@er+'e o? 18.>mont!. lini$+l mptom in$lu"e inomni+ or "irupte" leep. Mo$lonu, +t+Li+,"+rt!ri+, "p!+'i+, +n" pr+mi"+l i'n, +n" +utonomi$ !per+$ti@+tion $+n +lo benote". *e@erit +n" eDuen$e o? $lini$+l mptom m+ "i??er bet4een 129 MM +n" 129M= 'enotpe. nomni+, mo$lonu +n" +utonomi$ "?un$tion +re o?ten more e@erein 129 MM ube$t, 4!ile +t+Li+, "+rt!ri+ +n" ei<ure o?ten pre"omin+te in 129 M=ube$t I28,29,>>,>5,>7J.

Polomno'r+p! i @er ue?ul ?or t!e "i+'noi o? t!e "ie+e. t pro@i"e e@i"en$e o?inomni+ b "ipl+in' m+re" re"u$tion in leep time +n" "ior"erl tr+nition bet4eenleep t+'e. !e 129 M= 'enotpe i no4n to re"u$e t!e e@erit o? t!ee i'n o?+bnorm+l leep. n $ontr+t, t!e 129 M= 'enotpe i +o$i+te" 4it! more 4i"epre+"!pomet+bolim in t!e t!+l+mu +n" $in'ul+te $orteL + re@e+le" b poitron emiiontomo'r+p! (P). !u, P m+ be +not!er ue?ul tool ?or t!e "i+'noi o? . it!l+ter $erebr+l $orti$+l +n" $erebell+r in@ol@ement, neuron+l lo +n" +tro'lioi o$$ur














































pre"omin+ntl in t!e +nterior +n" "orome"i+n t!+l+mi$ nu$lei in +ll $+e +n" in t!ein?erior oli@e in mot $+e 4it! $+nt PrP "epoition. Ho4e@er, PrP "epoit m+ bemore e@i"ent in t!e mole$ul+r l+er o? t!e $erebellum 4it! + trip lie p+ttern +n" in t!eubi$ulum entor!in+l re'ion I28,29,>>,>5,>7J.

&poradic fatal insomnia <s3I=

A por+"i$ ?orm o? ?+t+l inomni+ () 4+ reporte" in 1999. !e p+tient !o4e"$lini$+l +n" neurop+t!olo'i$+l i'n imil+r to but ?+mil !itor +n" mut+tion in PRNP 4ere not e@i"ent. All p+tient 4ere 129 MM !omo<'ote +n" bio$!emi$+l tr+intpin' o? t!ee "ie+e ubtpe re@e+le" t!e onl "i??eren$e in t!e intenit o? t!eun'l$ol+te" ?r+'ment o? PrP*$ tpe 2; t!e un'l$ol+te" ?r+'ment 4+ un"errepreente" in I25,>5,>8J. *o ?+r, ne+r 2> $+e +ll re@e+lin' 129 MM!omo<'oit +n" prop+'+tin' PrP*$ tpe 2 !+@e been reporte" in @+riou $ountrie o? t!e4orl" I>9J. i o$$+ion+ll +lo re?erre" to + g-#MM2 t!+l+mi$g but i$lini$op+t!olo'i$+ll u??i$ientl "itin$t ?rom -#MM2. n -#MM2, $erebr+l $orteL

i mot e@erel +??e$te" r+t!er t!+n t!+l+mu 4!ere poibl t!e $ir$+"i+n r!t!m o?leep4+e $$le +re $ontrolle" I>2,>5J. Ho4 t!e +me MM2 PrP*$ en$o"e "itin$t p!enotpe in -# +n" i + m+tter o? $on$ern, in"i$+tin' t!+t ?+$tor +""ition+l tot!e $o"on 129 'enotpe +n" PrP*$ tpe m+ +lo be in@ol@e" in t!e "etermin+tion o? priontr+in. Ho4e@er, MM2 PrP*$ $on?ormer +o$i+te" 4it! -# +n" m+ !o4@+ri+tion in t!e intenit +n" i<e o? t!eir ?r+'ment b t!e +ppli$+tion o? more eniti@e2"imenion+l ele$trop!oreti$ ep+r+tion +n" impro@e" P "i'etion $on"ition I>2J.

3amilial or genetic $J" <f0g$J"=

+mili+l -# (?-#) i +o$i+te" 4it! "omin+ntl in!erite" point mut+tion in PRNP .

!ere i + re'ion o? 5 repe+t 4it!in PrP ?rom rei"ue 5191 $omprie" o? + non+pepti"ePOGGGGGO +n" ?our t+n"em o$t+pepti"e repe+t (PHGGGGO)>. nertion o? 29o$t+pepti"e repe+t (29EP) +n" + "eletion o? 2 o$t+pepti"e repe+t (2EP#) in PRNP +re +lo +o$i+te" 4it! u$eptibilit to ?-#. /e$+ue more t!+n 50U o? ?-#$+e !+@e been reporte" 4it!out + poiti@e ?+mil !itor o? t!e "ie+e, t!e termg'eneti$ -# ('-#)g i no4 bein' ue" more ?reDuentl inte+" o? ?-#. !ere i mu$!@+ri+tion in t!e penetr+n$e o? "i??erent mut+tion + e@i"en$e" b $oni"er+bleintr+?+mili+l +n" intr+'ener+tion+l p!enotpi$ @+ri+bilit; ometime, t!e "ie+e m+ip + 'ener+tion. !e in$i"en$e o? '-# i 515U o? +ll -# $+e. Alt!ou'! t!e?+mili+l n+ture o? '-# i no4n in$e 1920, mut+tion +o$i+te" 4it! t!e "ie+e 4ere?irt reporte" in 1989 onl 2 e+r +?ter t!e $lonin' o? PRNP $#A I28,29,>2,>>,>7,50J.

!e ?reDuen$ o? mut+tion "i??er 4orl"4i"e; !o4e@er, 'eo'r+p!i$+l or et!ni$ $lutero? '-# $+e 4it! mut+tion 200, 210=, #178, +n" =180 !+@e been reporte"?rom r+el, *lo@+i+, !ile, t+l, *p+in +n" -+p+n I>2,51J.

*imil+r to -#, t!e $lini$op+t!olo'i$+l p!enotpe in '-# l+r'el $orrel+te 4it! t!e$o"on 129 'enotpe +n" PrP*$ tpe, +n" mut+tion +ppe+r to pl+ + role not more t!+n +u$eptibilit ?+$tor. !et!er PRNP polmorp!im ot!er t!+n M129= +lo in?luen$e t!e"ie+e $!+r+$teriti$ i unno4n. Multiple tr+in, +lt!ou'! et rem+in uni"enti?ie",






















































m+ be in@ol@e" in t!e p+t!o'enei o? t!e "ie+e. or ome '-# $+e, ?r+'ment o?1218.5 #+ in +""ition to ?r+'ment o? 19 +n" 21 #+ 4!i$! $!+r+$teri<e PrP*$ tpe 2+n" 1, repe$ti@el, $+n +lo be ?oun". PRNP mut+tion m+ pl+ t!eir p+rt in t!e p+t!o'enei o? '-# b i) in$re+in' t!e propenit o? PrP +n" PrPM ?or +''re'+tion, ii)in$re+in' t!e retention o? +''re'+te" PrP mole$ule 4it!in e$retor p+t!4+, +n" iii)

mo"ul+tin' t!e intr+mole$ul+r +ltbri"'e +n" !"ro'en bon" inter+$tion. #iturb+n$e inintr+mole$ul+r inter+$tion i no4n to proe$t t!e !"rop!obi$ +mino +$i" outi"em+in' t!e protein inoluble I>>J. it! in$re+e o? e@er EP, bot! t!e +bilit o? PrPM

?or bin"in' "i@+lent ion u$! + $opper +n" t!e e@erit o? $lini$op+t!olo'i$+l p!enotpe+re in$re+e". !e bio$!emi$+l tr+in tpin' o? '-# o?ten re@e+l t!eun"errepreent+tion o? un'l$ol+te" ?r+'ment. !i i be$+ue un'l$ol+te"?r+'ment +re more unt+ble t!+n mono +n" "i'l$ol+te" ?r+'ment +n" +re, t!ere?ore,more ine??i$ient in t!eir tr+nport ?rom e$retor p+t!4+ to t!e pl+m+ membr+neI>2,>>,52J. Alt!ou'! $lini$+l p!enotpe rel+te" to mot o? mut+tion o@erl+p 4it! t!oeo? -# I>2J, t!e $lini$+l p!enotpe in '-# $+e $+rrin' t!e 18%A129M !+plotpei li'!tl "itin$ti@e +n" in$orpor+te peron+lit $!+n'e ?ollo4e" b r+pi"l

pro'rei@e "ementi+, 4it! ?rontotempor+l ?e+ture u$! + +''rei@e be!+@ior,!peror+lit, @erb+l tereotpe +n" o?ten p+rinoni+n i'n I5%J.

Gerstmann-&tr>ussler-&cheinker syndrome <G&&=

Autoom+l "omin+nt in!erit+n$e o? PRNP mut+tion m+ +lo le+" to +not!er ?orm o?!um+n * n+me" + Gertm+nn*trùler*$!einer *n"rome (G**). !e in$i"en$eo? G** i 1 in 100 million o? popul+tion per e+r I28J. G** i $!+r+$teri<e" b +n e+rlonet bet4een %0 +n" 60 e+r o? +'e +n" lo4 "ie+e pro'reion eLten"e" o@er + perio" o? %.59.5 e+r. lini$+l mptom 4!i$! m+ !o4 intr+?+mili+l +n"intr+'ener+tion+l @+ri+tion in$lu"e $erebell+r +t+Li+, '+it +bnorm+litie, "ementi+,

"+rt!ri+, o$ul+r "metri+, in?reDuent mo$lonu, p+ti$ p+r+p+rei, p+rinoni+ni'n, +n" !pore?leLi+ or +re?leLi+ in t!e lo4er eLtremitie I28,29J. Ho4e@er, le'!perre?leLi+ ?rom +n e+rl "ie+e $oure !+ re$entl been een in + -+p+nee G** p+tient $+rrin' t!e P1023 mut+tion I5>J. n G**, +ltere" leep +n" temper+ture r!t!mm+ +lo be noti$e" I55J. !e PRNP polmorp!im M129= !+ been !o4n to in?luen$et!e "ie+e p!enotpe. !en line" to =129 +llele, P1023, 4!i$! i t!e mot $ommon$+ue o? G**, reulte" in t!e pre"omin+n$e o? p$!i+tri$ i'n u$! + +p+t! +n""epreion I56J. G i r+rel "i+'noti$ in G**. ollo4in' PRNP mut+tion !+@e been!o4n to $oe're'+te 4it! G**: P1023, P1053, A117=, Y1>5^, O160^, 198*, O217,Y218, Y226^ +n" O227^ I28,29,57J. Y218 "emontr+te" $lini$+l $riteri+ ?or poibleAl<!eimer "ie+e +n" poible ?rontotempor+l "ementi+, 4it! neuro?ibrill+r

"e'ener+tion on neurop+t!olo'i$+l pro?ile, +n" @+riou PrP

*$

?r+'ment in t!e r+n'e o?1080 #+ I58J. n 'ener+l, neurop+t!olo'i$ ?e+ture o? G** p+tient in$lu"e numerou+mloi" pl+Due, e@ere to +bent pon'i?orm $!+n'e, neuron+l lo, +tro$ti$mi$ro'lioi, +n" @+ri+ble nuero?ibrill+r t+n'le I28,29,59J.

Iatrogenic $J" <i$J"=












































+tro'eni$ -# (i-#) 4+ ?irt "e$ribe" in 197> in + peron 4!o re$ei@e" $+"+@eri$$orne+l tr+npl+nt ?rom + p+tient o? -# I22J. *e@er+l $+e o? !um+n prion "ie+e, in$et!en, !+@e been +o$i+te" 4it! i+tro'eni$ tr+nmiion o? -# b t!e ue o? tereot+$ti$intr+$erebr+l G nee"le or neurour'i$+l intrument, $+"+@eri$ "ur+ m+ter 'r+?t +n"intr+mu$ul+r ine$tion o? $ont+min+te" $+"+@eri$ pituit+r"eri@e" !um+n 'ro4t!

!ormone (!GH) +n" 'on+"otrop!in !ormone. !e !i'!et proportion o? i-# $+e i+ttribute" to tre+tment 4it! !GH +n" 3o"ur+ 'r+?t pro"u$e" b /. /r+un Melun'enAG o? Germ+n +n" pro$ee" be?ore M+ 1987. Mot o? -# $+e line" to tre+tment4it! !GH !+@e o$$urre" in r+n$e, 4!ile t!oe line" to tre+tment 4it! "ur+ m+ter 'r+?t!+@e m+inl o$$urre" in -+p+n I28,29,51,60J. /et4een t!e l+te 1950 +n" 1985, +bout%0,000 $!il"ren 4ere tre+te" 4it! !GH 4orl"4i"e, +n" t!e o@er+ll proportion o? -#$+e ?rom t!e tre+te" popul+tion !+ been etim+te" to be +bout 1&100. t i belie@e" t!+tt!e liel PrP*$ $ont+min+tion o? pituit+r"eri@e" !GH +n" "ur+ m+ter 'r+?t reulte"?rom t!e pr+$ti$e o? b+t$! pro$ein'. /e?ore t!e pro"u$tion o? re$ombin+nt !GH, it 4++ p!+rm+$euti$+l pr+$ti$e to pro$e 5,00020,000 $+"+@eri$ pituit+r 'l+n" in + in'le b+t$! ?or t!e eLtr+$tion o? t!e !ormone. !e preen$e in t!e b+t$! o? + ?e4 pituit+r

'l+n" ?rom unno4n -# $+e m+ be reponible ?or $ont+min+tion. it! t!e+@+il+bilit o? re$ombin+nt !GH +n" t!e initi+tion o? ep+r+te" pro$ein' o? in"i@i"u+l"ur+ m+ter 'r+?t in$e 1987, t!e prob+bilit o? o$$urrin' ?uture i-# $+e +ppe+r to be@er lo4. A pe+ in t!e in$i"en$e o? i-# $+e 4it! lon' in$ub+tion perio" m+ o$$ur,!o4e@er I28,29,60J.

!e $lini$op+t!olo'i$+l ?e+ture o? -# line" to tre+tment 4it! !GH reemble 4it!t!oe o? uru. !e 129 MM !omo<'oit i + ri ?+$tor +n" in$ub+tion perio" m+ bein t!e r+n'e o? >.5 to o@er 25 e+r 4it! + me+n o? 12 e+r I28,29,60,61J. n $ontr+t, t!e$lini$op+t!olo'i$+l ?e+ture o? -# line" to neuro'r+?tin' o? "ur+ m+ter or t!e ue o?neurour'i$+l intrument reemble 4it! t!oe o? -#. !e me+n "ur+tion o? illne i

18 mont! +n" t!e in$ub+tion perio" m+ be in t!e r+n'e o? 1.518 e+r 4it! + me+n o?+bout 6 e+r. n -+p+n, t!e minimum ri o? "e@elopin' i-# !+ been etim+te" to be+pproLim+tel 1&%000 3o"ur+ 'r+?t re$ipient I28,29,60J.

/uru

uru i t!e ?irt !um+n prion "ie+e t!+t 4+ !o4n to be tr+nmiible to $!imp+n<ee b intr+$erebr+l intro"u$tion o? br+in !omo'en+te ?rom uru p+tient I62J. uru !+o$$urre" eL$lui@el in t!e ore lin'uiti$ 'roup o? P+pu+ e4 Guine+ +ternHi'!l+n" +n" t!e nei'!borin' people 4it! 4!om t!e interm+rrie". !ere 4+ + pr+$ti$e +mon' t!ee 'roup to $onume t!e "e+" bo"ie o? t!eir rel+ti@e + + m+r o?

repe$t +n" mournin' (ritu+liti$ $+nnib+lim). omen +n" oun' $!il"ren o? bot! eLe4ere more eLpoe" to t!e ri m+teri+l u$! + br+in +n" @i$er+ t!+n +"ult men 4!ouu+ll !+" pre?erenti+ll to $onume mu$le. !e uru epi"emi$ ille" 12U o? t!e popul+tion +t it pe+. *ome @ill+'e be$+me e@en "e@oi" o? +"ult 4omen. it! + b+n onritu+liti$ $+nnib+lim in t!e mi"1950 impoe" b Autr+li+n +ut!oritie, t!e in$i"en$eo? t!e "ie+e t+rte" to "e$line te+"il. uru 4+ intro"u$e" to etern me"i$ine in l+te1950, +lt!ou'! t!e ?irt $+e o? uru 4+ ober@e" +roun" 1920. !e etern $ientit4ere @er oon +ble to pro@e ritu+liti$ $+nnib+lim + t!e etiolo' o? t!e "ie+e. !e











































ol"er uru p+tient 4!o eLperien$e" +n eLpoure to t!e in?e$tion be?ore t!e b+n $+n till be een. !e in$ub+tion perio" o? uru in u$! p+tient 4oul" be more t!+n 50 e+rI27,59,6%65J. uru !+ impoe" tron' ele$tion preure in t!e +??e$te" ore 'roup on PRNP epe$i+ll +t $o"on 127 +n" 129. Hetero<'oit +t t!ee PRNP $o"on i +reit+n$e ?+$tor ?or uru +n" $+n be een 4it! m+re" pre@+len$e +mon' ur@i@or o? t!e

uru epi"emi$ I27,65J.

uru !+ % $lini$+l t+'e n+mel +mbul+nt (till $+n 4+l), e"ent+r (onl $+n it up),+n" termin+l (un+ble to it up in"epen"entl). An ill"e?ine" pro"rom+l perio"$!+r+$teri<e" b !e+"+$!e +n" p+in uu+ll in t!e oint o? le' m+ pre$e"e t!ee t+'e.erebell+r +t+Li+, tremor +n" $!orei?orm +n" +t!etoi" mo@ement +re "itin$ti@e +n" prominent $lini$+l i'n. *!i@erin' +mpli?i+ble b $ol" 4+ t!e mptom on t!e b+i o?4!i$! t!e "ie+e 4+ n+me" gurug. !e mot prominent $lini$+l ?e+ture o? -#, t!e"ementi$ illne $+n +lo o$$ur in ome $+e but it !+ppen "urin' t!e ?in+l "ie+et+'e onl. europ+t!olo'i$+l ?e+ture u$! + pon'ioi, neuron+l lo, +n" +tro$ti$mi$ro'lioi $+n @+ri+bl be ober@e" in * uu+ll in t!e 're m+tter. !e PrP*$

"epoition i ober@e" in * onl I59,6%J. !e neurop+t!olo'i$+l propert 4!i$!"itin'ui!e uru ?rom -# i t!e preen$e o? numerou uru pl+Due, p!eri$+l bo"ie4it! + rim o? r+"i+tin' ?il+ment. uru i belie@e" to be $+ue" b t!e $onumption o? +-# $+e +n" eLperiment+l tr+nmiion tu"ie !+@e !o4n imil+rit bet4een t!emole$ul+r +n" p+t!obiolo'i$+l propertie o? prion $+uin' uru, -# +n" i-# I66J.*imil+r tu"ie !+@e +lo re@e+le" "i??eren$e in tr+nmiion "n+mi$, perip!er+l p+t!o'enei +n" t!e neurop+t!olo' propertie o? uru +n" @-# prion. A bot! uru+n" @-# +re $+ue" b in?e$tion @i+ or+l route, t!ee "i??eren$e $+n be +ttribute" to t!etr+in tpe r+t!er t!+n t!e route o? in?e$tion I6%J. Ho4e@er, + re$ent tu" !o4e" t!+t-#, /* +n" $r+pie +'ent 4ere e@i"entl "i??erent ?rom t!e uru +'ent in in$ub+tiontime, br+in neurop+t!olo', +n" t!e lmp!oreti$ul+r in@ol@ement. !e +ut!or $on$lu"e"

t!+t gt!e 'eo'r+p!i$ in"epen"en$e o? t!e uru +'ent pro@i"e +""ition+l re+on toeLplore $+u+l en@ironment+l p+t!o'en in t!ee in?e$tiou neuro"e'ener+ti@e "ie+egI67,68J.

,ariant $J" <7$J"=

!e ?irt 10 p+tient o? ne4 @+ri+nt or impl o? @+ri+nt -# (n@-#&@-#) 4erereporte" in April 1996 in I2>,60J. !e +'e o? t!ee p+tient 4+ rel+ti@el oun'er bet4een 16 +n" %9 e+r +n" t!e m+ni?ete" + pre"omin+n$e o? p$!i+tri$ mptominte+" o? $erebell+r +t+Li+ or pro'rei@e "ementi+ I60J. About 219 @-# $+e !+@e been reporte" !it!erto ?rom 8 urope+n +n" > nonurope+n $ountrie (*A, +n+"+,

*+u"i Ar+bi+, +n" -+p+n). !e mot o? @-# $+e (172) !+@e been reporte" ?rom +lone I69J. P$!i+tri$ +n" be!+@ior+l mptom o? @-# m+ in$lu"e +'it+tion,+''reion, "epreion, +nLiet, +p+t!, emotion+l l+bilit, inomni+, poor $on$entr+tion, p+r+noi" "eluion, re$lene, or 4it!"r+4+l; + $ombin+tion o? t4o or more o? t!eemptom +ppe+r in mot o? t!e p+tient. *ome p+tient m+ +lo !o4 i'n o? enor"iturb+n$e u$! + p+in, p+ret!ei+, +n" "et!ei+. !e neurolo'i$ mptom o$$ur +tle+t 6 mont! +?ter t!e onet o? p$!i+tri$ mptom +n" in$lu"e $erebell+r +t+Li+,$o'niti@e imp+irment, in@olunt+r mo@ement 4!i$! m+ be "toni$, $!orei?orm or




































mo$loni$. n$ontinen$e o? urine, pro'rei@e immobilit, +n" +ineti$ mutim +re t!el+te onet i'n. #e+t! o?ten o$$ur be$+ue o? inter$urrent in?e$tion. !e me+n +'e +tonet o? mptom i 29 e+r, +n" t!e pro'reion or tot+l "ur+tion o? t!e "ie+e p+n18 mont! in +@er+'e, 4!i$! i imil+r to t!+t i reporte" ?or uru +n" i-# line" totre+tment 4it! !GH I28,29,60J. Gener+li<e" lo4in' o? G +$ti@it +n" +n in$re+e in

t!e le@el o? 1>%% protein in * m+ be "i+'noti$ o? @-# in more t!+n 50U o? t!e$+e. Ho4e@er, t!e ober@+tion o? poterior t!+l+mi$ !i'! i'n+l $!+r+$teri<e" bNpul@in+rN or N!o$e ti$N i'n on 2 "i??uion or l+ir 4ei'!te" M im+'in' +n" t!e"ete$tion o? PrPre in tonill+r biop +re import+nt ?or t!e pe$i?i$ "i+'noi o? t!e"ie+e I29,70J.

!e neurop+t!+lo'i$+l !+llm+r o? @-# i t!e preen$e o? urutpe +mloi" pl+Dueurroun"e" b pon'i?orm leion gt!e ?lori" pl+Dueg 4!i$! +lo !+@e been een in$r+pie but ne@er in ot!er !um+n prion "ie+e I28,29,60J. *pon'i?orm $!+n'e o$$urmot e@i"entl in t!e b++l '+n'li+ +n" t!+l+mu 4it! p+re "itribution t!rou'!out t!e$erebr+l $orteL. !e ?lori" pl+Due +n" PrPre immuno!ito$!emi$+l t+inin' !+@e

o$$urre" pre"omin+ntl in t!e $erebellum +n" $erebrum I28J. Ho4e@er, u??i$ient+mount o? PrPre +re "ete$te" in t!e lmp!oreti$ul+r tem o? @-# p+tient I60J. !e"ete$tion o? PrPre in t!e lmp!oreti$ul+r tem !+ $on?i"entl been ue" ?or t!e"i+'noi o? @-# e@en in $lini$+ll norm+l ube$t ($+rrier) I71J. o "+te, +ll @-# p+tient !+@e been 129 MM !omo<'ote I72J.

=er oon +?ter t!e report on 10 @-# $+e, epi"emiolo'i$+l tu"ie, eLperiment+ltr+nmiion o? t!e "ie+e to $nomolo'ou m+$+Due +n" mi$e (4il" + 4ell +tr+n'eni$) +n" bio$!emi$+l tr+in tpin' line" t!e etiolo' o? @-# to in?e$tion ?rom/* prion I60J. !e +me or "i@ere p!enotpe m+ "e@elop on prim+r +n" e$on"+rtr+nmiion o? @-# +n" /* to mi$e eLprein' !um+n PrP, "epen"in' on t!e our$e

o? ino$ulum +n" t!e PrP eDuen$e o? t!e re$ipient, +n" t!e 129 M= !etero<'ote m+ bele reit+nt to @-# tr+nmiion + $omp+re" to /* tr+nmiion I7%,7>J. !e 219 !etero<'oit 4!i$! !+ been $oni"ere" + ri ?+$tor ?or tr+nmiion o? /* to!um+n m+ $on?er reit+n$e to @-# tr+nmiion 4it!in !um+n I70,75J. Moreo@er, +tle+t > p+t!olo'i$+ll $on?irme" $+e in$lu"in' 1 4it! ub$lini$+l or potenti+ll pre$lini$+l in?e$tion !+@e been +o$i+te" 4it! t!e e$on"+r @-# tr+nmiion @i+ bloo" tr+n?uion I76J. !ee report on e$on"+r i+tro'eni$ tr+nmiion +n" t!e poibilit o? @-# o$$urren$e 4it! lon' in$ub+tion perio" in in"i@i"u+l 4it! 129 M=+n" 129 == PrP 'enotpe !+@e r+ie" eriou publi$ !e+lt! $on$ern I71,72,77,78J.*ome $+e o? uru +n" i-# !+@e o$$urre" +?ter in$ub+tin' t!e "ie+e ?or +lmot 50+n" %0 e+r, repe$ti@el I6%,6>,76,79J.

,ariably protease-sensiti7e prionopathy <,P&Pr=

n 2008, + no@el ?orm o? +tpi$+l "ementi+ 4+ "emontr+te" in 11 p+tient, +ll o? 4!om4ere 129 == !omo<'ote +n" mot o? 4!om re@e+le" + poiti@e ?+mil !itor ?or$o'niti@e imp+irment. o mut+tion in PRNP +""ition+l to t!e M129= polmorp!im 4+"ete$te". !e $lini$+l $oure o? t!e "ie+e 4+ 2 e+r lon'er t!+n -# butneurop+t!olo'i$+l pro?ile 4ere "i+'noti$ o? *. A more "itin$ti@e ?e+ture b+e" on






























































4!i$! t!e "ie+e 4+ n+me" initi+ll + gprote+eeniti@e prionop+t!g (P*Pr) 4+ t!ere"u$e" reit+n$e o? PrP#i io?orm to proteoli b P. !e proteoli o? PrP#i

io?orm b P reulte" in more t!+n % PrP#i ?r+'ment. Ampli?i$+tion b PMA +n"tr+nmiibilit to +nim+l mo"el o? PrP#i et rem+in to be in@eti'+te" I26,>2J. !eetu"ie 4ill +lo in?orm on mole$ul+r me$!+nim o? t!e "ie+e p+t!o'enei.

*imil+r to -#, P*Pr $+n be een in in"i@i"u+l !+rborin' +n o? % M129= 'enotpe(129 MM, 129 M= +n" 129 ==). A t!e eniti@it o? PrP#i io?orm to tre+tment 4it!P 4+ @+ri+ble +$$or"in' to t!e $o"on 129 'enotpe, t!e "ie+e 4+ ren+me" +g@+ri+bl prote+eeniti@e prionop+t!g (=P*Pr). !e PrP#i ?rom 129 == $+e 4+more eniti@e to P tre+tment t!+n 4+ PrP#i ?rom 129 MM $+e, 4it! PrP#i ?rom 129M= $+e !o4in' interme"i+r P eniti@it I80J. Moreo@er, b+e" on t!e $o"on 129'enotpe, t!e PrP#i $on?ormer ?rom =P*Pr $+e not onl !o4e" "i??erenti+limmunore+ti@it to mono$lon+l +ntibo"ie r+ie" +'+int @+riou PrP epitope but +lo@+rie" in t!e intenit (r+tio) o? in"i@i"u+l ?r+'ment. !et!er t!e $o"on 129 'enotpe+re +o$i+te" 4it! "itin$t $lini$+l p!enotpe, neurop+t!olo'i$+l leion +n"

!itolo'i$+l "itribution o? PrP

#i

rem+in to be elu$i"+te". o "+te, %0 $+e 4it! =P*Prin$lu"in' 20 o? 129 ==, 7 o? 129 M= +n" % o? 129 MM PRNP 'enotpe !+@e beenreporte" ?rom @+riou $ountrie I>2,8082J. A$$or"in' to t!i "+t+, t!e PRNP 'enotpe129 MM +ppe+r prote$ti@e +'+int t!e "e@elopment o? =P*Pr I>2J.

Go to:

$onclusion

!e epi"emi$ o? uru, i+tro'eni$ -# +n" @-# !+@e re+$!e" t!eir en" I8%J. Ho4e@er,por+"i$ +n" 'eneti$ $+e o? !um+n prion "ie+e +re o$$urrin' 4orl"4i"e 4it! +n

+nnu+l pre@+len$e o? 12 $+e per million o? popul+tion. Amon' 'eneti$ !um+n prion"ie+e, G** preent pre"omin+ntl + +n +mloi"op+t!. !ere i no $ure ?or t!ee"ior"er. Mot o? "e@elopin' $ountrie in$lu"in' P+it+n !+@e no epi"emiolo'i$+lin?orm+tion on !um+n prion "ie+e. e !+@e re$entl per?orme" t!e +n+li o? PRNPin 909 unrel+te" P+it+ni in"i@i"u+l. An inertion o? % o$t+pepti"e repe+t (%EP)4+ ?oun" in !etero<'ou t+te in +n in"i@i"u+l +n" t!e eLtent o? !omo<'oit +t t!e129 $o"on 4+ 6%U. !ee reult in"i$+te t!+t P+it+ni popul+tion i u$eptible to prion "ior"er I8>J. !e o$t+pepti"e repe+t re'ion o? !um+n PRNP $onit o? 5 repe+t4!i$! +re "ei'n+te" + 1 t!rou'! 5. ? +n nu$leoti"e @+ri+tion i ?oun" 4it!in +repe+t, t!e n+me o? t!+t nu$leoti"e i +""e" to t!e n+me o? $orrepon"in' repe+t i.e., 2+or %' I85J. A %EP (1, 2, 2, %', 2, 2, %, >) line" to 219 +llele in one

peron (68 e+r ol") +n" to 129 = +llele in +not!er (69 e+r ol") !+ been +o$i+te"4it! ?&'-# I86,87J. A %EP (1, 2, 2, 2+, 2, 2, %, >) line" to 129 M +llele!+ +lo been "ete$te" in + $lini$+ll norm+l !inee oun' 'irl +n" !er mot!er 4!o 4+in !er l+te %0N I85J.

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Abbre7iations

PRNP : Prion protein 'ene; PrP: Prion protein; PrP: ellul+r io?orm o? prion protein;PrP*$: *$r+pie io?orm o? prion protein; PrPM: Mut+nt PrP; *(): r+nmiiblepon'i?orm en$ep!+lop+t!(ie); -#: ruet<?el"t-+$ob "ie+e; -#: *por+"i$ -#;

@-#: =+ri+nt -#; ?&'-#: +mili+l&'eneti$ -#; i-#: +tro'eni$ -#; : +t+l?+mili+l inomni+; G**: Gertm+nn*tr+uler*$!einer n"rome; : *por+"i$ ?+t+linomni+; P*Pr: Prote+eeniti@e prionop+t!; =P*Pr: =+ri+bl prote+eeniti@e prionop+t!; M: r+nmiible min en$ep!+lop+t!; #: !roni$ 4+tin' "ie+e;/*: /o@ine pon'i?orm en$ep!+lop+t!; : Loti$ un'ul+te pon'i?ormen$ep!+lop+t!; *: eline pon'i?orm en$ep!+lop+t!; HP: * in non!um+n prim+te; EP: E$t+pepti"e repe+t; EP: nertion o? o$t+pepti"e repe+t; EP#:#eletion o? o$t+pepti"e repe+t; GP: Gl$olp!op!+ti"linoitol; *: entr+lner@ou tem; G: le$troen$ep!+lo'r+p!; *: erebropin+l ?lui"; : omputer tomo'r+p!; M: M+'neti$ reon+n$e im+'in'; P: Poitron emiion tomo'r+p!;P: Protein+e ; $#A: omplement+r #A; !GH: Hum+n 'ro4t! !ormone; re:

eit+nt; #i: #ie+e; b: ilo b+e; #+: ilo #+lton; ++: Amino +$i"; A: Al+nine;#: Ap+rti$ +$i"; : Glut+mi$ +$i"; : P!enl+l+nine; G: Gline; H: Hiti"ine; :oleu$ine; : 3ine; 3: 3eu$ine; M: Met!ionine; : Ap+r+'ine; P: Proline; O:Glut+mine; : Ar'inine; *: *erine; : !reonine; =: =+line; : rptop!+n; ^: *top$o"on; Y: roine.

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$ompeting interests

!e +ut!or "e$l+re t!+t t!e !+@e no $ompetin' interet.

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Authors? contributions

M1 ur@ee" liter+ture +n" 4rote t!e +rti$le. *M2 or'+ni<e" t!e $ontent +n" ubmitte"t!e +rti$le. All +ut!or re+" +n" +ppro@e" t!e ?in+l m+nu$ript.

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75. Hi<ume M, ob++!i A, eru+ , E!+!i H, roni"e -, Mo!ri *, it+moto .Hum+n prion protein (PrP) 219 i $on@erte" to PrP*$ but !o4 !etero<'ouin!ibition in @+ri+nt reut<?el"t-+ob "ie+e in?e$tion. - /iol !em.2009;28>:%60%–%609. IPubMe"J

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http://dx.doi.org/10.1073%2Fpnas.0800190105







http://dx.doi.org/10.4161%2Fviru.1.2.10822


http://dx.doi.org/10.1007%2Fs00103-010-1070-7


http://dx.doi.org/10.1001%2Farchneurol.2010.184



http://dx.doi.org/10.1136%2Fbmj.332.7551.1164



http://dx.doi.org/10.1186%2F1471-2350-10-146








http://dx.doi.org/10.1016%2FS0140-6736(06)69835-8












http://dx.doi.org/10.1007%2Fs00103-010-1070-7


http://dx.doi.org/10.1001%2Farchneurol.2010.184






http://dx.doi.org/10.1186%2F1471-2350-10-146








http://dx.doi.org/10.1016%2FS0140-6736(06)69835-8



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http://dx.doi.org/10.1016%2FS0140-6736(09)61568-3

http://dx.doi.org/10.1016%2FS0140-6736(09)61568-3










http://dx.doi.org/10.1186%2F1471-2377-10-99




http://dx.doi.org/10.1016%2Fj.gene.2011.10.029


http://dx.doi.org/10.1038%2Fsj.ejhg.5201245


http://dx.doi.org/10.1007%2Fs10048-004-0196-x





http://dx.doi.org/10.1016%2FS0140-6736(09)61568-3

http://dx.doi.org/10.1016%2FS0140-6736(09)61568-3










http://dx.doi.org/10.1186%2F1471-2377-10-99




http://dx.doi.org/10.1016%2Fj.gene.2011.10.029


http://dx.doi.org/10.1038%2Fsj.ejhg.5201245





Jurnal @

*olecular-Imaging Probe 6-<1-B-C<6-

3luoroethyl=<*ethyl= AminoD-6-NaphthylE%thylidene= *alononitrile

'abels Prion Pla9ues In Vitro

1. M+r+ /re+n+$1,2,2. 3o<e M. *mi"1,2,%. om+< #. =o@o1,2,>. An"re Petrij%,5. -or'e . /+rrio>, +n"

6. M+r+ Popo@i$2

[ Aut!or A??ili+tion

1. 1 L'-or'$or/ or N&*ron'! P!'%$"#"$/ 'n0 R&&n&r'$"on In%$"$*$& o

P'$op/%"o!o/ 2 Pr"on L'-or'$or/ In%$"$*$& o P'$o!o/ S#oo! o M&0"#"n&'n0 3 4'#*!$/ o C&("%$r/ 'n0 C&("#'! T&#no!o/ Un".&r%"$/ o L5*-!5'n' SI6

1777 L5*-!5'n' S!o.&n"' 'n0 D"."%"on o N*#!&'r M&0"#"n& D&p'r$(&n$ o

Mo!&#*!'r 'n0 M&0"#'! P'r('#o!o/ L'-or'$or/ o S$r*#$*r'! B"o!o/ 'n0

Mo!&#*!'r M&0"#"n& Un".&r%"$/ o C'!"orn"' Lo% An&!&% S#oo! o M&0"#"n& Lo% An&!&% C'!"orn"' 9779

eLt *e$tion

Abstract

!e tu" +ime" to e@+lu+te t!e ?luore$ent mole$ul+rim+'in' probe 2(1k6I(2?luoroet!l)(met!l)+minoJ2n+p!t!let!li"ene)m+lononitrile (##P) ?or it +bilitto ele$ti@el +n" repro"u$ibl l+bel prion pl+Due in ?iLe", p+r+??inembe""e" $erebell+r e$tion ?rom p+tient o? $on?irme" Gertm+nn*trùler*$!einer "ie+e, por+"i$reut<?el"t-+$ob "ie+e (-#) 4it! uru pl+Due, +n" @+ri+nt -# (@-#). ##P i +!i'!l !"rop!obi$, @i$oiteniti@e, ol@enteniti@e, ?luore$ent ubt+n$e, 4!oe

r+"io?luorin+te" +n+lo' I18J##P !+ re$entl been u$$e?ull ue" to l+bel enile pl+Due +n" neuro?ibrill+r t+n'le in t!e li@in' br+in o? Al<!eimerN "ie+e p+tient 4it! poitron emiion tomo'r+p!. Eur reult !o4 t!+t ##P reli+bl i"enti?ie +ll prion pl+Due, in$lu"in' m+ll $luterpl+Due in @-#. !i ?in"in' m+ open ne4 "n .".o "i+'noti$ poibilitie ?or @-#.

• fluorescent labeling

• human

http://www.jneurosci.org/search?author1=Mara+Bresjanac&sortspec=date&submit=Submit

http://www.jneurosci.org/content/23/22/8029.long#target-1


http://www.jneurosci.org/search?author1=Lojze+M.+Smid&sortspec=date&submit=Submit



http://www.jneurosci.org/search?author1=Tomaz+D.+Vovko&sortspec=date&submit=Submit



http://www.jneurosci.org/search?author1=Andrej+Petri%C4%8D&sortspec=date&submit=Submit


http://www.jneurosci.org/search?author1=Jorge+R.+Barrio&sortspec=date&submit=Submit


http://www.jneurosci.org/search?author1=Mara+Popovic&sortspec=date&submit=Submit


http://www.jneurosci.org/content/23/22/8029.long

http://www.jneurosci.org/content/23/22/8029.long#sec-1

http://www.jneurosci.org/search?fulltext=%0A++++++++fluorescent+labeling%0A++++++&sortspec=date&submit=Submit&andorexactfulltext=phrase

http://www.jneurosci.org/search?fulltext=%0A++++++++human%0A++++++&sortspec=date&submit=Submit&andorexactfulltext=phrase

http://www.jneurosci.org/search?author1=Mara+Bresjanac&sortspec=date&submit=Submit



http://www.jneurosci.org/search?author1=Lojze+M.+Smid&sortspec=date&submit=Submit



http://www.jneurosci.org/search?author1=Tomaz+D.+Vovko&sortspec=date&submit=Submit



http://www.jneurosci.org/search?author1=Andrej+Petri%C4%8D&sortspec=date&submit=Submit


http://www.jneurosci.org/search?author1=Jorge+R.+Barrio&sortspec=date&submit=Submit


http://www.jneurosci.org/search?author1=Mara+Popovic&sortspec=date&submit=Submit


http://www.jneurosci.org/content/23/22/8029.long


http://www.jneurosci.org/search?fulltext=%0A++++++++fluorescent+labeling%0A++++++&sortspec=date&submit=Submit&andorexactfulltext=phrase

http://www.jneurosci.org/search?fulltext=%0A++++++++human%0A++++++&sortspec=date&submit=Submit&andorexactfulltext=phrase



• neuroimaging

• T&%

• 7ariant $reutfeldt-Jacob disease

• amyloid

Pre@iou *e$tion eLt *e$tion

Introduction

r+nmiible pon'i?orm en$ep!+lop+t!ie (*), +lo no4n + prion "ie+e, +re +'roup o? in@+ri+bl ?+t+l neuro"e'ener+ti@e "ior"er t!+t +??e$t bot! !um+n +n" +nim+l(Pruiner, 1998). #epite t!eir r+rit ( 1 $+e per million per e+r), !um+n * !+@e +∼

"r+m+ti$ imp+$t be$+ue o? t!eir $lini$+l pro?ile +n" $omplete +ben$e o? e??e$ti@etre+tment. on$ern o? poible tr+nmiion o? prion "ie+e t!rou'! ur'i$+l +n""ent+l pro$e"ure, tiue tr+npl+nt+tion, +n" bloo" tr+n?uion !+@e been ?uele" b +re$ent emer'en$e o? + ne4 @+ri+nt reut<?el"t-+$ob "ie+e (@-#) (ill et +l., 1996)

+n" e@i"en$e o? it +o$i+tion 4it! t!e epi"emi$ o? bo@ine pon'i?orm en$ep!+lop+t!.

#e?initi@e "i+'noi o? + prion "ie+e reDuire + potmortem p+t!omorp!olo'i$+linpe$tion o? t!e br+in, 4!i$! i uu+ll $ombine" 4it! immunolo'i$+l "ete$tion +n"$!+r+$teri<+tion o? t!e p+t!olo'i$+l prion protein PrP*$ (#eArmon" et +l., 2002). !ere+re $urrentl + ?e4 +ntemortem in@eti'+tion t!+t $+n $onoli"+te + $lini$+l upi$ion o?+ prion "ie+e (e.'., G, m+'neti$ reon+n$e br+in im+'in', immuno++ ?or + r+n'eo? nonpe$i?i$ m+rer). one o? t!em, !o4e@er, !+ +n i"e+l eniti@it +n" pe$i?i$it pro?ile. n p+rti$ul+r, t!ee in@eti'+ti@e te$!niDue "o not +ppe+r to be "e$ii@e ine$urin' t!e "i+'noi o? @-#. !ere?ore, in@+i@e pro$e"ure (i.e., * orlmp!oreti$ul+r tiue biop) !+@e been ue" to $on?irm t!e preen$e o? PrP*$ in

upe$te" @-# (roni"e et +l., 2002).

e$entl, /+rrio et +l. (1999) "e@elope" 2(1k6I(2I18J?luoroet!l) (met!l)+minoJ2n+p!t!let!li"ene)m+lononitrile (I18J##P; I18J, $ 1&2 F 110 min) ?or poitronemiion tomo'r+p! (P) $+n "ete$tion o? +mloi" "epoit in Al<!eimerN "ie+e(A'"epp+ et +l., 2001). More re$entl, + mo"i?ie" @erion o? t!io?l+@in l+bele" 4it! 11($ 1&2 F 20 min) 4+ +lo intro"u$e" 4it! imil+r intent (/+$+i et +l., 2002). I18J##P$roe t!e bloo"br+in b+rrier +n" re@e+l t!e lo$+li<+tion +n" lo+" o? enile pl+Due +n"neuro?ibrill+r t+n'le in t!e li@in' br+in o? Al<!eimerN "ie+e p+tient (A'"epp+ et +l.,2001; *!o'!i-+"i" et +l., 2002). A P mole$ul+r im+'in' probe t!+t $oul" imil+rlre@e+l prion pl+Due 4oul" be p+rti$ul+rl rele@+nt ?or t!e "i+'noi o? @-#, in 4!i$!

m+i@e prion pl+Due +re + !+llm+r o? t!e "ie+e +n" !+@e + $!+r+$teriti$ "itribution4it!in t!e * (ill et +l., 1996; ei"ler et +l., 1997; #eArmon" et +l., 2002; roni"e et+l., 2002).

##P i + !"rop!obi$ ubt+n$e t!+t bin" to it li'+n" t!rou'! !"rop!obi$inter+$tion (A'"epp+ et +l., 2001). t $+n be eL$ite" in t!e @iible p+rt o? t!e pe$trum bet4een >>0 +n" >90 nm. t ?luore$ent emiion i en@ironment+ll eniti@e, bein' poorl ?luore$ent in 4+ter +n" o? $oni"er+bl tron'er ?luore$en$e 4!en in @i$ou

http://www.jneurosci.org/search?fulltext=%0A++++++++neuroimaging%0A++++++&sortspec=date&submit=Submit&andorexactfulltext=phrase

http://www.jneurosci.org/search?fulltext=%0A++++++++TSE%0A++++++&sortspec=date&submit=Submit&andorexactfulltext=phrase

http://www.jneurosci.org/search?fulltext=%0A++++++++variant+Creutzfeldt-Jacob+disease%0A++++++&sortspec=date&submit=Submit&andorexactfulltext=phrase

http://www.jneurosci.org/search?fulltext=%0A++++++++amyloid%0A++++++&sortspec=date&submit=Submit&andorexactfulltext=phrase

http://www.jneurosci.org/content/23/22/8029.long#abstract-1


http://www.jneurosci.org/content/23/22/8029.long#ref-12

















http://www.jneurosci.org/search?fulltext=%0A++++++++neuroimaging%0A++++++&sortspec=date&submit=Submit&andorexactfulltext=phrase

http://www.jneurosci.org/search?fulltext=%0A++++++++TSE%0A++++++&sortspec=date&submit=Submit&andorexactfulltext=phrase

http://www.jneurosci.org/search?fulltext=%0A++++++++variant+Creutzfeldt-Jacob+disease%0A++++++&sortspec=date&submit=Submit&andorexactfulltext=phrase

http://www.jneurosci.org/search?fulltext=%0A++++++++amyloid%0A++++++&sortspec=date&submit=Submit&andorexactfulltext=phrase

http://www.jneurosci.org/content/23/22/8029.long#abstract-1




















en@ironment, or 4!en boun" (-+$obon et +l., 1996; Petri$ et +l., 1998; A'"epp+ et +l.,2001; *!o'!i-+"i" et +l., 2002). A(1>0) ?ibrilboun" ##P pe+ emiion i +t

500 nm (∼ A'"epp+ et +l., 2001).

!e +im o? t!i tu" 4+ to ue t!e nonr+"io+$ti@e ##P +n" "etermine it "n ."$ro

potenti+l ?or pl+Due l+belin' in !um+n prion "ie+e 4it! +mloi" pl+Due, 4it! p+rti$ul+r emp!+i on @-#.


*aterials and *ethods

*e$tion o? p+r+?orm+l"e!"e?iLe", p+r+??inembe""e" !um+n $erebell+r +mple ?rom p+tient 4it! $on?irme" por+"i$ -# (-#) 4it! uru pl+Due, Gertm+nn*trùler*$!einer (G**) n"rome (4it! t!e P1023 mut+tion o? t!e PRNP 'ene; 'eneroul pro@i"e" b #r. Herbert /u"+, ntitute o? eurolo', ni@erit o? =ienn+, +n"

Autri+n e?eren$e entre ?or Hum+n Prion #ie+e, =ienn+, Autri+; H+in?ellner +t +l.,1995), +n" @-# ('eneroul pro@i"e" b #r. -+me roni"e, europ+t!olo'3+bor+tor, -# *ur@eill+n$e nit, ni@erit o? "inbur'!, "inbur'!, ) 4ere ue"in t!e tu". n +""ition, tiue e$tion o? eDu+ll pro$ee" br+in o? + "e$e+e"in"i@i"u+l (norm+l $ontrol) no4n not to !+@e !+" + prion "ie+e or +n ot!erneurolo'i$+l "ior"er 4+ ue" + + ne'+ti@e $ontrol. !e -# +n" @-# (but not G** or norm+l) $erebell+r +mple 4ere immere" in 96U ?ormi$ +$i" ?or 1 !r +?ter ?iL+tion in p+r+?orm+l"e!"e.

!e 5mt!i$ e$tion 4ere eit!er ue" imme"i+tel +?ter "ep+r+??in+tion or +?ter+nti'en retrie@+l pro$e"ure in@ol@in' %0 min +uto$l+@in' +t 121 in "itille" 4+ter +n"

ubeDuent 5 min in$ub+tion in 96U ?ormi$ +$i", 4!i$! i t!e t+n"+r" re$ommen"e" pretre+tment ?or PrP *$ immuno"ete$tion in tiue +mple (He'i et +l., 1997).

Mono$lon+l +ntibo" (MAb) %> 4+ ue" (#+o, Glotrup, #enm+r) ?orimmuno?luore$ent () +n" immuno!ito$!emi$+l (H) "ete$tion o? PrP *$. /ot!immuno"ete$tion pro$e"ure 4ere in"ire$t, uin' biotinl+te" e$on"+r +ntibo" +n"trept+@i"in?luorop!ore $onu'+te () or +@i"inbiotinperoLi"+e 4it! %_,%"i+minoben<i"ine (H). /rie?l, t!e e$tion 4ere rine" in bu??er be?ore + >U norm+l!ore erum 4+ +pplie" in bu??er, pH 7.2, ?or 20 min to blo$ t!e nonpe$i?i$ bin"in' o?t!e e$on"+r +ntibo". n$ub+tion 4it! t!e prim+r +ntiPrP MAb %> (%10 '&ml) 4+ per?orme" o@erni'!t +t >. n$ub+tion in t!e biotinl+te" !ore +ntimoue e$on"+r

+ntibo" (1:1000; =e$tor 3+bor+torie, /urlin'+me, A) 4+ ?ollo4e" b in$ub+tion int!e +@i"inbiotinperoLi"+e $ompleL (A/ *t+n"+r" lite it; =e$tor 3+bor+torie) +n"$!romo'en (%_,%"i+minoben<i"ine; *i'm+, #eien!o?en, Germ+n) olution, ortrept+@i"inAleL+ >88 (Mole$ul+r Probe, u'ene, E). n H, !em+toLilin$ountert+inin' 4+ ue" to @iu+li<e t!e $ell nu$lei.

##P 4+ nt!ei<e" + "e$ribe" pre@ioul (A'"epp+ et +l., 2001). 3+belin' 4+ per?orme" on "ep+r+??in+te" e$tion t+ine" 4it! !em+toLilin, rine" in 4+ter, +n"




























immere" ?or 5 min in 1U *u"+n bl+$ olution in 70U et!+nol to re"u$e t!e+uto?luore$en$e o? lipo?u$in (*$!nell et +l., 1999) +n" ot!er tiue $omponent.*e$tion 4ere rine" 4it! 4+ter, +n" eL$e *u"+n bl+$ 4+ remo@e" b "ippin' t!eli"e in 70U et!+nol. !e e$tion 4ere t!en in$ub+te" 4it! + ?re!l prep+re" 10 m##P in +Dueou 1U et!+nol (@&@) in t!e "+r +t room temper+ture (A'"epp+ et +l.,

2001). !e t+ine" tiue 4+ rine" 4it! 4+ter +n" $o@erlippe" 4it! 'l$erol be?ore@ie4in' un"er t!e ?luore$ent mi$ro$ope.

3+belin' o? t!e +me pl+Due 4it! ##P +n" %> immuno?luore$en$e 4+ per?orme"in eDuen$e, +n" t!e ##P 4+ +pplie" ?irt to + ?re!l "ep+r+??in+te" e$tion. !et+ine" e$tion 4+ p!oto'r+p!e", rine" in et!+nol to remo@e ##P, +n" pretre+te" ?or immuno"ete$tion o? PrP *$ +''re'+te, + "e$ribe" +bo@e. /e?ore +pplin' %> to t!eee$tion, 4e @eri?ie" t!+t no rem+inin' ##P ?luore$en$e 4+ "ete$te" in t!e pl+Due.n t!e ?in+l erie, e$tion 4ere ?irt t+ine" 4it! ##P, p!oto'r+p!e", rine" inet!+nol, +n" t+ine" 4it! perio"i$ +$i"*$!i?? (PA*). PA* 4+ $!oen o@er t!e more+mloi"pe$i?i$ on'o re" t+inin' be$+ue o? t!e better l+belin' pro?ile o? m+ller

pl+Due 4it! t!e ?ormer "e. A?ter $olle$tion o? p!oto'r+p! o? t!e PA*t+ine" pl+Due,4e eLpoe" t!e +me e$tion to t!e +nti'en retrie@+l proto$ol +n" pro$ee" t!em ?orH "ete$tion o? PrP *$ 4it! %>.

P!otomi$ro'r+p! 4ere t+en on + ion $lipe 600 li'!t +n" ?luore$ent mi$ro$opeeDuippe" 4it! +ppropri+te ?ilter (^ >65695, #M 505, /A 515555), 4it! + ion#^M 1200 "i'it+l $+mer+, +n" $onne$te" to + peron+l $omputer im+'e +n+li t+tion.M# m+'e An+li *tem o?t4+re (m+'e An+li *tem, *t. +t!+rine, Ent+rio,+n+"+) 4+ ue" to i"enti? in"i@i"u+l pl+Due, to @eri? t!eir l+belin' 4it! "i??erentte$!niDue, +n" to "etermine t!e i'n+l ur?+$e +re+ in ##P, PA*, +n" %>Hl+bele" e$tion. /rie?l, + mi$ro$opi$ im+'e 4+ "i'iti<e", +n" + i'n+l t!re!ol" 4+

"etermine" ?or e+$! o? t!e l+belin' met!o" +pplie" to t!e +me lo$i (n F > ?iel" +t 200m+'ni?i$+tion). !e i'n+l ur?+$e +re+ 4+ t!en me+ure", +n" ##P +n" PA* reult4ere eLpree" + per$ent+'e (+@er+'e S *#) o? t!e %>H me+urement reult. in+lim+'e 4ere $re+te" b peu"o$olorin' t!e ori'in+l 'reen ?luore$ent i'n+l ello4 in+$$or"+n$e 4it! t!e reDuirement ?or "i'it+l +rt prep+r+tion.


esults

3""NP identifies typical prion pla9ues in human prion diseases

*t+n"+r" H re@e+le" "i@ere prion +''re'+te in t!e $erebell+r tiue e$tion ?rom +llt!e prion "ie+e $+e ue" in t!i tu": + uru pl+Due in -# (i'. 1'), multi$entri$ pl+Due in G** (i'. 1#), +n" tpi$+l pie"b+ll pl+Due in @-# (i'. 1&). n +"+$ente$tion, "i??erent prion pl+Due 4ere $onitentl +n" intenel l+bele" 4it! ##P int!e +me p+ttern $!+r+$teriti$ ?or e+$! o? t!e t!ree prion "ie+e (i'. 1- 0 , +n" ,repe$ti@el). A imult+neoul pro$ee" e$tion ?rom + norm+l $erebellum (i'. 1 6")"ipl+e" no "ete$t+ble ?luore$ent l+belin' 4it! ##P (i'. 1 5).






http://www.jneurosci.org/content/23/22/8029.long#F1



























=ie4 l+r'er @erion:• n t!i p+'e

• n + ne4 4in"o4

• #o4nlo+" + Po4erPoint *li"e

i'ure 1.

' -, omp+rion o? t+n"+r" immuno!ito$!emitr +n" ##P pl+Due l+belin'. H4it! %> MAb re@e+l tpi$+l prion +''re'+te in t!e $erebell+r tiue e$tion ?rom +llt!e prion "ie+e $+e ue" in t!i tu": uru pl+Due in -# ('), multi$entri$ pl+Duein G** (-), +n" tpi$+l pie"b+ll pl+Due in @-# (#). #i??erent prion pl+Due !o4intene l+belin' 4it! ##P in t!e +me 'ener+l p+ttern $!+r+$teriti$ ?or e+$! o? t!et!ree prion "ie+e (06 , repe$ti@el). 5, orm+l $ontrol $erebell+r e$tion t+ine" onl4it! !em+toLilin ( ) "ipl+ $oni"er+ble +uto?luore$en$e () t!+t 4+ Duen$!e" b*u"+n bl+$ t+inin' (" 5). n +""ition, +ben$e o? ?luore$ent i'n+l +?ter ##Pl+belin' o? t!e +me e$tion i !o4n in 5. Green ?luore$ent i'n+l 4+ peu"o$olore"ello4. *$+le b+r: ' , 50 m; 5, 15 m.

3""NP pla9ue identification is confirmed by prion-specific

immunolabeling

*eDuenti+l +ppli$+tion o? prion immunol+belin' +n" ##P to t!e +me tiue e$tion permitte" + "ire$t $ontrol o? prion pl+Due "ete$tion +n" l+belin' 4it! ##P. Aben$e o? +nti'en retrie@+l te$!niDue pre$lu"e u$$e?ul immuno"ete$tion o? mot prion+''re'+te 4it! +ntiPrP +ntibo"ie on ?orm+l"e!"e?iLe", p+r+??inembe""e" tiuee$tion. !u, !+r! +nti'en retrie@+l !+ to be ue" to +llo4 optim+l immuno"ete$tion

o? prion +''re'+te (He'i et +l., 1997). *u$! tiue pretre+tment 4+ "etermine" not to be $omp+tible 4it! ##P pl+Due l+belin' ("+t+ not !o4n). !ere?ore, ##P 4++pplie" ?irt onto ?re!l "ep+r+??in+te" e$tion +n" ?oun" to ele$ti@el +n"repro"u$ibl l+bel prion pl+Due o? @+riou i<e, in$lu"in' m+ller $luterpl+Due in@-# $erebell+r e$tion (i'. 2'). ##P bin"in' i re@erible, +n" no pl+Due?luore$en$e $oul" be "ete$te" +?ter e@er+l et!+nol rine ut be?ore %> MAb+ppli$+tion to t!e +me e$tion (i'. 2-). "ete$tion o? prion +''re'+te 4it! %> +t t!e+me lo$+tion pre@ioul l+bele" 4it! ##P re@e+le" + Du+lit+ti@el @er imil+r

http://www.jneurosci.org/content/23/22/8029/F1.expansion.html


http://www.jneurosci.org/powerpoint/23/22/8029/F1

















=ie4 l+r'er @erion:• n t!i p+'e

•

n + ne4 4in"o4

• #o4nlo+" + Po4erPoint *li"e

i'ure %.

omp+rion o? $one$uti@e l+belin' o? t!e +me lo$u o? + in'le tiue e$tion 4it!##P (', ello4 peu"o$olore" pl+Due), PA* (-, m+'ent+l+bele" pl+Due), +n" Hto PrP*$ (#, bro4n pre$ipit+te). ##P l+bele" bot! l+r'er +mloi" +n" m+ller $luter pl+Due, 4!ere+ PA* re+"il i"enti?ie motl l+r'er +mloi" pl+Due. ??e$ti@e +nti'enretrie@+l +n" i'n+l +mpli?i$+tion o? prion immunol+belin' 4it! +ntiPrP MAb +llo4

@iu+li<+tion o? +ll prion "epoit o@er + 4i"e +re+ in t!e +me lo$+tion. *$+le b+r, 200m.

!e "i??eren$e bet4een pl+Due l+belin' te$!niDue @iible in i'ure 2 +n" % 4ererou'!l Du+nti?ie" b eLprein' ##P +n" PA*l+bele" ur?+$e +re+ + per$ent+'e o? t!e ur?+$e +re+ o? t!e +me tiue e$tion l+bele" 4it! %>H: ##P i'n+l ur?+$e+re+ 4+ 16 S >U, 4!ere+ PA* i'n+l ur?+$e +re+ $o@ere" 6 S 2U o? t!e ur?+$e +re+l+bele" 4it! %>H.


"iscussion

!i tu" +ime" to e@+lu+te t!e ?luore$ent mole$ul+r probe ##P ?or it +bilit toele$ti@el +n" repro"u$ibl l+bel prion pl+Due in ?iLe", p+r+??inembe""e" $erebell+re$tion ?rom p+tient o? $on?irme" G**, -# 4it! uru pl+Due, +n" @-#. Eur reult!o4 t!+t ##P reli+bl i"enti?ie prion pl+Due in +ll tiue +mple. t +bilit toele$ti@el "ete$t prion pl+Due o? @+riou i<e in t!e tete" tiue +mple 4+$on?irme" b i"enti?i$+tion o? t!e +me pl+Due 4it! + t+n"+r" +ntiPrP +ntibo",%>. n @-# +mple, ##P +llo4e" "ete$tion o? m+ller pl+Due better t!+n PA*t+inin' o? t!e +me prion +''re'+te, 4!i$! 4+ $on?irme" b ubeDuent H "ete$tiono? t!e ?ull eLtent o? PrP*$ "epoit +t t!e +me lo$u o? in"i@i"u+l tiue e$tion.

Amyloid pla9ues in prion diseases

!e protein onl !pot!ei t+te t!+t t!e in?e$tiou +'ent $+uin' * i +$on?orm+tion+l iomer o? PrP, + !ot protein, t!e ?un$tion o? 4!i$! i till poorlun"ertoo" (Pruiner, 1998). !e p+t!olo'i$+l iomer, PrP*$, !+ !i'! !eet $ontent, il+r'el prote+ereit+nt, +n" ?orm +''re'+te, 4!i$! +$$umul+te in t!e br+in (Pruiner,1998). #i??erent tpe o? prion +''re'+te +n" t!eir +n+tomi$+l "itribution +re







http://www.jneurosci.org/content/23/22/8029.long#fn-group-1











http://www.jneurosci.org/content/23/22/8029.long#fn-group-1






$!+r+$teriti$ ?or "i??erent prion "ie+e (#eArmon" et +l., 2002). Alt!ou'! prion"epoit $+n be o? @+riou i<e +n" tru$ture, prion ?reDuentl ?orm +mloi" pl+Due,4!i$! +re + !+llm+r o? ome prion "ie+e u$! + G**, -# 4it! uru pl+Due, +n"@-# (#eArmon" et +l., 2002). !e l+tter "ie+e i + prime $+n"i"+te $on"ition ?ornonin@+i@e "n .".o pro$e"ure, 4!i$! 4oul" +i" "i+'noi.

&uspected 7$J"4 a diagnostic challenge

urrentl, t!e $lini$+l $oure i e to et+bli!in' + 4orin' "i+'noi o? @-#.motion+l +n" be!+@ior+l $!+n'e o$$ur e+rl in @-# +n" ?reDuentl in@ol@e "epreionor p$!oi. !e l+$ o? m+re" or'+ni$ ?e+ture o?ten le+" to + p$!i+tri$ "i+'noi(ei"ler et +l., 1997). !e upi$ion o? @-# i r+ie" i? +t+Li+ +n" ?or'et?ulne "e@elop(ei"ler et +l., 1997). #i+'noi o? @-# m+ be $on?irme" b "ete$tin' PrP*$ in bioppe$imen, but t!e nonuni?orm tiue "itribution o? tpi$+l ?lori" pl+Due in t!e *+n" lo4 $on$entr+tion o? PrP*$ in lmp!oreti$ul+r tiue !+ o$$+ion+ll reulte" inne'+ti@e biop reult (roni"e et +l., 2002). !u, "e?initi@e "i+'noi reDuire +

potmortem "ete$tion o? e@ere pon'i?orm $!+n'e in t!e b++l '+n'li+, t!+l+mu, +n"$erebellum, + 4ell + t!e preen$e o? prion pl+Due.

!e mot rem+r+ble ?e+ture o? @-# i t!e obli'+tor m+i@e +mount o? prion +mloi" pl+Due, m+n 4it! ?e+ture o? uru pl+Due, +n" t!e !u'e number o? primiti@e pl+Duelie "epoit t!+t +re PA* nonre+$ti@e (#eArmon" et +l., 2002). All re'ion o? t!e$erebr+l $orteL $ont+in prion pl+Due, but t!e !i'!et $on$entr+tion o$$ur in t!e$erebellum (#eArmon" et +l., 2002; roni"e et +l., 2002). !ere?ore, + P $+n probe,4!i$! 4oul" reli+bl +n" eniti@el l+bel prion pl+Due in br+in o? li@in' p+tient,4oul" be o? 're+t potenti+l @+lue.

Potential for molecular-imaging of amyloid pla9ues with C1F

3D3""NP-P%Tin vivo

A mole$ul+r probe u$! + ##P t!+t bin" to +mloi" pl+Due 4it! !i'! +??init(A'"epp+ et +l., 2001; *!o'!i-+"i" et +l., 2002) i liel to meet t!e reDuirement o?u??i$ient eniti@it. ##P i + !"rop!obi$ mole$ule t!+t ?orm in"u$e" "ipole bet4een t!e "onor 'roup (e.'., "i+ll +mino) +n" +$$eptor moiet (e.'., m+lononitrile) in@+riou en@ironment+l $on"ition. e !pot!ei<e t!+t t!ee "ipole 4oul" ?orm!"ro'en bon" inter+$tion 4it! 'roup on t!e !"rop!obi$ ur?+$e o? +mloi"+''re'+te (or t+u +''re'+te in neuro?ibrill+r t+n'le), 'i@in' rie to t!e uniDue bin"in' propertie o? t!i ne4 probe. ##P i not t!e onl mole$ul+r probe t!+t !+ been

"e@elope" ?or t!e purpoe o? "n .".o neuroim+'in' o? +mloi" pl+Due (/+$+i et +l.,2002; un' et +l., 2002). Ho4e@er, I18J##P it i t!e onl ubt+n$e t!+t !+" beenu$$e?ull ue" to lo$+li<e +n" +e t!e bur"en o? enile pl+Due +n" neuro?ibrill+rt+n'le in li@in' br+in o? Al<!eimerN p+tient.

!e l+$ o? pe$i?i$it o? ##P ?or prion pl+Due o@er +mloi" pl+Due o? Al<!eimerN"ie+e, or ot!er +mloi" "epoit in t!e br+in, mi'!t be @ie4e" + +n +pp+rent"i+"@+nt+'e. Ho4e@er, +n in"i$+tion ?or + pl+Due"ete$tin' P $+n in + $+n"i"+te





























@-# p+tient 4oul" be b+e" on + t!orou'! $lini$+l e@+lu+tion +n" p+tient !itor, t!u$oni"er+bl re"u$in' t!e lieli!oo" o? $on?uin' @-# 4it! ot!er "ie+e 4it! +mloi""epoition in t!e br+in, u$! + Al<!eimerN "ie+e. urt!ermore, + prepon"er+n$e o? pl+Due lo+" in t!e $erebellum 4oul" "itin'ui! t!e P $+n reult o? + @-# p+tient?rom @irtu+ll +ll "i??erenti+l "i+'noe.

3""NP labels all ;3@-identified prion pla9ues in vitro

n our tu", ##P 4+ $omp+re" 4it! one o? t!e routine !itolo'i$+l met!o" ?or+mloi" t+inin', PA* (#eArmon" +t +l., 2002). !en +pplie" to + e$tion o? @-#$erebell+r tiue, ##P 4+ !o4n to l+bel not onl l+r'e +mloi" pl+Due but +lom+ll $luterpl+Due t!+t 4ere not reli+bl @iu+li<e" 4it! ubeDuent +ppli$+tion o?PA* onto t!e +me e$tion. t !+ been !o4n pre@ioul t!+t $ert+in pl+Due, in p+rti$ul+r t!e m+ller $luterpl+Due repreentin' + i'ni?i$+nt proportion o? pl+Due lo+"in @-#, "o not "ipl+ tpi$+l tin$tori+l propertie o? +mloi" (e.'., t!e +re noteoinop!li$ or PA* re+$ti@e) (#eArmon" +t +l., 2002).

!ere?ore, in +""ition to $omp+rin' ##P 4it! PA*, 4e +lo tete" t!e +bilit o?##P to i"enti? pl+Due +'+int optimi<e" immuno"ete$tion o? prion "epoit b +t+n"+r" +ntiPrP MAb, %>. !e intent 4+ to obt+in + rou'! Du+ntit+ti@e +ement o?t!e proportion o? +ll prion "epoit t!+t $+n be "ete$te" b ##P. Eur reult $le+rl!o4 t!+t ##P l+bele" +ll pl+Due t!+t 4ere ubeDuentl i"enti?ie" b +mpli?ie"immuno?luore$en$e o? t!e +ntiPrP +ntibo" bin"in'. !e ober@e" "i??eren$e in t!eintenit o? l+belin' b ##P +n" %> immuno?luore$en$e !oul" be interprete" int!e $onteLt o? t!e "i??eren$e in t!e i'n+l +mpli?i$+tion bet4een t!e t4o met!o". e o? PrPpe$i?i$ +ntibo"ie on +"eDu+tel prep+re" tiue +n" +ppropri+te i'n+l+mpli?i$+tion te$!niDue +llo4 @iu+li<+tion o? mot, e@en t!e ?inet (e.'., n+pti$) prion

"epoit. n $ontr+t, ##P !oul" be eLpe$te" to +$$umul+te pre"omin+ntl in t!oe pl+Due 4it! +mloi" ultr+tru$ture. =iu+li<+tion o? m+ll PA*non"ete$t+ble pl+Due4it! ##P (ubeDuentl $on?irme" 4it! %> bin"in') re@e+l + ?+@or+ble prion pl+Duel+belin' pro?ile o? ##P.

Prion "ete$tion 4it! %> immuno?luore$en$e +n" ##P 4ere bot! ome4!+t limite" b t!e +uto?luore$ent b+$'roun" o? +l"e!"e?iLe" tiue, 4!i$! reDuire" Duen$!in'(*$!nell et +l., 1999). Ho4e@er, + le t!+n i"e+l i'n+ltonoie r+tio +ttribut+ble to tiue+uto?luore$en$e i +n +rti?+$t o? t!e "n ."$ro $on"ition un"er 4!i$! ##P 4+ tete"in t!i tu". +"iol+bele" ##P ue" + + P probe 4oul" not be liel to en$ountert!ee problem. !e l+tter t+tement $oul" be tete" "n ."$ro b "eterminin' t!e

pe$i?i$it +n" eniti@it o? prion +mloi" +''re'+te "ete$tion b + r+"iol+bele"##P. n +""ition, tr+n'eni$ mi$e (*$ott et +l., 1999) or prim+te (3+me<+ et +l.,2001) ino$ul+te" 4it! @-# !oul" be ue" to tet t!e I18J##P P $+n "ete$tion o? prion pl+Due "n .".o. in+ll, t!e preent e@i"en$e o? tron' "n ."$ro prion pl+Due l+belin'4it! ##P $ouple" 4it! t!e "o$umente" u$$e?ul +n" +?e ue o? I18J##P to"ete$t pl+Due lo+" in li@in' Al<!eimerN "ie+e p+tient (*!o'!i-+"i" et +l., 2002) $oul"timul+te prep+r+tion ?or t!e ?irt I18J##P P $+n o? $on?irme" +n" upe$te"@-# p+tient.



















B'rr"o ;R H*'n SC Co!& GM S'$/'(*r$/ N P&$r"# A P&!p% ME S('!! G<

=1999> PET I('"n o $'n!&% 'n0 p!'*&% "n A!&"(&r% 0"%&'%&+ ; N*#! M&0

7 F7P6F1P+

4. ↵

D&Ar(on0 S; Kr&$%#('r HA Pr*%"n&r SB =2772> Pr"on 0"%&'%&%+ InGr&&n"&!0% n&*rop'$o!o/ E0 F :o! 2 =Gr''( DI L'n$o% PE &0%> pp 2F36

323+ Lon0on Arno!0+

5. ↵

H'"n&!!n&r ;A Br'n$n&r6In$'!&r S C&r.&n)o. L Bron P K"$'(o$o T

T'$&"%" ; D"r"n&r H L"-&r%)" PP R&&!& H 4&*#$ M M'/r N <&%%&!/ P

S*((&r K S&"$&!-&r&r 4 B*0)' H =199> T& or""n'! G&r%$('nn6S$r*%%!&r6S#&"n)&r '("!/ o A*%$r"' 0".&r&n$ #!"n"#op'$o!o"#'! p&no$/p&% -*$

#on%$'n$ PrP &no$/p&+ Br'"n P'$o! 2716211+

Me"line

6. ↵

H&/" I H'"n&!!n&r ;A 4!"#)&r H Iron%"0& ;< H'* ;; T'$&"%" ; H'!$"' M B*"'n" O A*" A B*0)' H =199F> Pr"on pro$&"n "((*no#/$o#&("%$r/

r&!"'-!& %$'"n"n pro$o#o! "((*no(orpo!o/ 'n0 0"'no%$"# p"$'!!%+ C!"n

N&*rop'$o! 1? 2?262?3+

7. ↵

Iron%"0& ;< M#C'r0!& L Hor%-*r A L"( Z H&'0 M< =2772> P'$o!o"#'!

0"'no%"% o .'r"'n$ Cr&*$&!0$6;')o- 0"%&'%&+ APMIS 117 F968F+

roe?Me"line

8. ↵

;'#o-%on A P&$r"# A Ho&n)'(p D S"n*r A B'rr"o ;R =199?> 116D"#/'no626=?60"(&$/!'("non'p$'!&n626/!>prop&n& =DDNP> ' %o!.&n$ po!'r"$/6'n0

."%#o%"$/6%&n%"$".& !*oropor& or !*or&%#&n#& ("#ro%#op/+ ; A( C&( So# 118F26F9+

roe?

9. ↵

http://www.jneurosci.org/content/23/22/8029.long#xref-ref-4-1


http://www.jneurosci.org/external-ref?access_num=8520719&link_type=MED



http://www.jneurosci.org/external-ref?access_num=10.1034/j.1600-0463.2002.100110.x&link_type=DOI



http://www.jneurosci.org/external-ref?access_num=10.1021/ja9543356&link_type=DOI







http://www.jneurosci.org/external-ref?access_num=10.1034/j.1600-0463.2002.100110.x&link_type=DOI



http://www.jneurosci.org/external-ref?access_num=10.1021/ja9543356&link_type=DOI




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http://www.jneurosci.org/external-ref?access_num=10.1016/S0006-8993(02)03436-4&link_type=DOI



http://www.jneurosci.org/cgi/ijlink?linkType=ABST&journalCode=pnas&resid=98/7/4142


http://www.jneurosci.org/external-ref?access_num=10.1016/S0960-894X(98)00241-8&link_type=DOI





http://www.jneurosci.org/cgi/ijlink?linkType=ABST&journalCode=spjhc&resid=47/6/719








http://www.jneurosci.org/external-ref?access_num=10.1016/S0960-894X(98)00241-8&link_type=DOI





http://www.jneurosci.org/cgi/ijlink?linkType=ABST&journalCode=spjhc&resid=47/6/719





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Jurnal

Am - P+t!ol. 1999 o@ember; 155(5): 1>5%–1>57.PM#: PM186696>

&electi7e Neuronal ,ulnerability in

+uman Prion "iseases

+t+l +mili+l nomni+ #i??er ?rom Et!er pe o? Prion #ie+eM+rin Guent$!e@, -uli+ +n$!it<, ill =oi'tl`n"er , Hel'+ li$er , +n" Herbert /u"+Aut!or in?orm+tion C Arti$le note C opri'!t +n" 3i$ene in?orm+tion C

!i +rti$le !+ been $ite" b ot!er +rti$le in PM.Go to:

Abstract

Hum+n tr+nmiible pon'i?orm en$ep!+lop+t!ie (*) or prion "ie+e +reneuro"e'ener+ti@e "ior"er o? in?e$tiou, in!erite" or por+"i$ ori'in +n" in$lu"ereut<?el"t-+ob "ie+e (-#), Gertm+nn*trùler*$!einer "ie+e (G**), uru


http://www.jneurosci.org/external-ref?access_num=10.1176/appi.ajgp.10.1.24&link_type=DOI










http://www.ncbi.nlm.nih.gov/pubmed/?term=Guentchev%20M%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Wanschitz%20J%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Voigtl%26%23x000e4%3Bnder%20T%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Flicker%20H%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Budka%20H%5Bauth%5D









http://www.jneurosci.org/external-ref?access_num=10.1176/appi.ajgp.10.1.24&link_type=DOI









http://www.ncbi.nlm.nih.gov/pubmed/?term=Wanschitz%20J%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Flicker%20H%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Budka%20H%5Bauth%5D








+n" ?+t+l ?+mili+l inomni+ (). lini$op+t!olo'i$ ?e+ture o? "i??er m+re"l ?romot!er !um+n *. Pre@iou tu"ie "emontr+te" ele$ti@e neuron+l @ulner+bilit o? p+r@+lbumin poiti@e (P=[) GA/Aer'i$ in!ibitor interneuron in por+"i$ -# +n"eLperiment+l *. n t!i report 4e !o4 uni?orm e@ere lo o? P=[ neuron +lo inot!er * u$! + G**, uru, ne4 @+ri+nt +n" ?+mili+l -#. n $ontr+t, t!ee neuron

+re motl 4ell preer@e", or onl mo"er+tel re"u$e", in . Enl P=[ neuronurroun"e" b iole$tin/> poiti@e perineuron+l net 4ere e@erel +??e$te" in *,u''etin' + ?+$tor rei"in' in t!i tpe o? eLtr+$ellul+r m+triL +roun" P=[ neuron +mo"ul+tor ?or t!e ele$ti@e neuron+l @ulner+bilit.

r+nmiible pon'i?orm en$ep!+lop+t!ie (*) or prion "ie+e +reneuro"e'ener+ti@e "ior"er o? in?e$tiou, in!erite", or por+"i$ ori'in (?or re@ie4 eee?. 1% ). Hum+n * in$lu"e reut<?el"t-+ob "ie+e (-#), Gertm+nn*trùler*$!einer "ie+e (G**), uru, +n" ?+t+l ?+mili+l inomni+ (). -# i tr+"ition+ll$+te'ori<e" into t!e mot $ommon por+"i$ + 4ell + i+tro'eni$, ?+mili+l (?-#) +n"ne4 @+ri+nt (n@-#) "ie+e, 4!i$! emer'e" in t!e p+t e+r in t!e nite" in'"om. >

*pon'i?orm $!+n'e, +tro'lioi, +n" neuron+l lo +re t!e $l+i$+l neurop+t!olo'i$+ltri+" o? tiue leion in *. !ere+ -#, G**, +n" uru "ipl+ o@erl+ppin' $lini$+l+n" neurop+t!olo'i$+l ?e+ture, t!e $lini$+l preent+tion +n" neurop+t!olo'i$+l !+llm+ro? i'ni?i$+ntl "i??er ?rom +ll ot!er !um+n *. 5

e$ent tu"ie !+@e ober@e" ele$ti@e @ulner+bilit o? "itin$t neuron+l ubet inpor+"i$ -#, eLperiment+l -#, +n" eLperiment+l $r+pie. !ee report !o4e" e+rl,e@ere +n" ele$ti@e lo o? p+r@+lbumin poiti@e (P=[) neuron, 6,7 4!i$! +re + ubet o?GA/Aer'i$ interneuron; $orrel+tion bet4een tiue p+t!olo' +n" "itribution o? P=[neuron, 8 +berr+nt neuropepti"e Y mA in"u$tion, +n" "e$re+e o? neuropepti"e Y Y2re$eptor bin"in' ite in t!e !ippo$+mpu o? $r+piein?e$te" mi$e. 9 !ee ubet

pe$i?i$ $!+n'e 4ere u''ete" + poible b+i ?or ome o? t!e $lini$+l mptom in*. Ho4e@er, ubetpe$i?i$ p+t!olo' !+ not been in@eti'+te" in !um+n * +p+rt?rom por+"i$ -#, u$! + G**, uru, , ?-#, +n" n@-#. n t!i tu", 4ein@eti'+te P=[ neuron in t!ee le $ommon tpe o? !um+n *.

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e ue" ?ormol?iLe", p+r+??inembe""e" !um+n br+in tiue obt+ine" +t +utop. i@e (t!ree m+le +n" t4o ?em+le p+tient, +'e r+n'e 26–56 e+r, prion protein (PrP) 'ene

( PRNP ) 'enotpe #178; ?our !omo<'ou +t t!e polmorp!i$ PRNP $o"on 129 ?ormet!ionine (M), one unno4n, in$lu"in' ?our $+e ?rom + ne4 Autri+n ?+mil reporte" pre@ioul 10,11 ), ?our G** (t4o m+le +n" t4o ?em+le p+tient, +'e r+n'e %7–62 e+r,4it! PRNP 'enotpe P1023 (>&>) +n" M129M (%&>, one unno4n); in$lu"in' t4o $+e?rom t!e ori'in+l Autri+n ?+mil reporte" pre@ioul 12 ), ?our ?-# 4it! t!e PRNP mut+tion 200 (t4o m+le +n" t4o ?em+le p+tient, +'e r+n'e 50–66 e+r, in$lu"in'one $+e 4it! $o"on =129= reporte" pre@ioul 1% ), 1 uru (16e+rol" m+le, =129=; H $+e in"l pro@i"e" b #r. P. 3iberi, 3o"<, Pol+n", reporte" pre@ioul 1> ), +n"

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1866964/#b1

























t4o n@-# $+e (51e+rol" m+le +n" 27e+rol" ?em+le, M129M; in"l pro@i"e" b#r. -. roni"e, "inbur'!, ; reporte" pre@ioul > ). !e ?ollo4in' re'ion 4erein@eti'+te": ?ront+l $orteL, $erebellum, !ippo$+mpu, +n" +"+$ent tempor+l $orteL.Hippo$+mp+l blo$ ?rom t4o n@-#, t4o ?-#, +n" one $+e 4ere not +@+il+ble?or in@eti'+tion. A $ontrol, ei'!t ?ormol?iLe" !um+n +utop br+in (?our m+le +n"

?our ?em+le p+tient, +'e r+n'e 27–66 e+r) 4it! norm+l !itolo' 4ere ue".

e per?orme" immuno!ito$!emitr ?or p+r@+lbumin (P=) +n" le$tin t+inin' 4it!iole$tin/> (3/>) to "e$or+te perineuron+l net (P) o? eLtr+$ellul+r m+triL +roun"P=[ neuron. 15 4o mono$lon+l +ntibo"ie +'+int P= (P=2%5, PA=19, bot! "ilute"1:5000, *i'm+ !emi$+l o., *t. 3oui, ME) 4ere ue". *e$tion ?or P= l+belin' 4ere boile" 10 minute in t+r'et retrie@+l olution (pH 9.9) (#+o, Glotrup, #enm+r). 3e$tint+inin' (3/>peroLi"+e l+bele", 10 '&ml ribu??ere" +line, 1 !our; *i'm+) 4+ per?orme" on e$tion boile" ?or 10 minute in $itr+tebu??ere" +line (pH 6.0). /ot! +ntiP= +ntibo"ie !o4e" + imil+r "itribution o? P=lie immunore+$ti@it, but t!e P=2%5immunot+ine" e$tion !+" + better i'n+l tob+$'roun" r+tio +n" t!u 4ere m+inl

ue" ?or e@+lu+tion.

Ou+nti?i$+tion 4+ m+"e blin"l b t4o o? u (M. G. +n" -. .). ountin' b bot!!o4e" @er imil+r reult; me+n @+lue 4ere entere" into ?in+l t+titi$+l e@+lu+tion.P=[ neuron 4ere +ee" in t!e +me re'ion (?ront+l +n" tempor+l $orteL) o? $ontrol,, G**, ?-#, +n" n@-# $+e b $ountin' immunopoiti@e $ell bo"ie in %repreent+ti@e ?iel" 4it! + 20 obe$ti@e. !e me+n o? +ll % ?iel" 4+ entere" intot+titi$+l e@+lu+tion. !e tot+l number o? neuron 4ere e@+lu+te" in Ht+ine"e$tion o? $ontrol, , G**, ?-#, +n" n@-# $+e b $ountin' uneDui@o$+l neuron+l$ell bo"ie in t!e % ?iel" eL+mine" 4it! + >0 obe$ti@e. !e me+n o? +ll % ?iel" 4+entere" into t+titi$+l e@+lu+tion. euron+l $ell bo"ie 4ere 4ell "itin'ui!+ble ?rom

t!e !omo'eneoul re" $topl+m o? re+$ti@e +tro$te, 4!i$! +re +bun"+nt in *.!e me+n re'ion+l number o? +ll +n" o? P=[ neuron 4ere $+l$ul+te" +n" tete" ?ori'ni?i$+nt "i??eren$e in +ll 'roup ($ontrol, , +n" ot!er *) uin' + ru+l+llione4+ ?ollo4e" b + t4ot+ile" M+nn!itne U tet.

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esults

$ontrols

ontrol !+" + imil+r pro?ile o? re'ionpe$i?i$ "itribution o? P=[ neuron, 4it! !i'!etnumber in pre +n" p+r+ubi$ulum, ?ront+l (i'ure 1A) +n" tempor+l $orteL, mo"er+tenumber in entor!in+l $orteL +n" ubi$ulum, +n" lo4 number in !ippo$+mp+l e$torA1–>. n t!e $erebellum, Purine $ell 4ere tron'l poiti@e ?or p+r@+lbumin (i'ure2) . euron 4it! 3/>[ P 4ere "itribute" in t!e $orteL +n" !ippo$+mp+l?orm+tion; in $ontr+t, 3/>[ P 4ere not "ete$t+ble +roun" Purine $ell (i'ure2A) . !e number o? 3/>[ P 4+ !i'!er in t!e ?ront+l $orteL t!+n in t!e tempor+l$orteL.









i'ure 1.P+r@+lbumin immunot+inin' (A.$: G.I) +n" iole$tin/> t+inin' ?or perineuron+l neto? eLtr+$ellul+r m+triL (".3: /.*) in ?ront+l $orteL in $ontrol (A: "), ((: %), G**($: 3), n@-# (G: / ), ?-# (+: '), +n" uru ( )))

i'ure 2.3/> t+inin' (A) o? + $ontrol $erebellum +n" p+r@+lbumin immunot+inin' o? + uru (()+n" $ontrol ($) $erebellum. !ere i l+$ o? 3/>[ P +roun" P=[ Purine $ell innorm+l br+in; Purine $ell +re preer@e" in uru. Eri'in+l m+'ni?i$+tion: )))

Gerstmann-&tr>ussler-&cheinker "isease: /uru: 3amilial: and New

,ariant $reutfeldt-Jakob "isease

All $+e !o4e" *pe$i?i$ p+t!olo': pon'i?orm $!+n'e, +tro'lioi, neuron+l lo(in t!e ?ront+l $orteL 22U S 2.% *M + $omp+re" to $ontrol) +n" PrP "epoition.∼

!ee "i??erent * tpe !o4e" + uni?orm ubtot+l to tot+l lo o? P=[ neuron +n"e@ere lo o? P= neuropil t+inin' in t!e ?ront+l ( 71U S 5.0 *M,∼ P 0.001; i'ure1, G, H, ; i'ure % ), tempor+l ( 57.>U S 16.7 *M,∼ P 0.02) +n" entor!in+l$orteL, pre +n" p+r+ubi$ulum +n" +ll re'ion o? t!e !ippo$+mpu, irrepe$ti@e o? t!elo$+l e@erit o? pon'i?orm $!+n'e or +tro'lioi. Enl one G** $+e !o4e" + norm+lnumber o? P=[ neuron in t!e tempor+l $orteL. !e lo o? P=[ neuropil +n" n+pti$ button +ppe+re" more e@ere t!+n t!e lo o? P=[ $ell bo"ie (i'ure 1, G, H, ) . !e

number +n" morp!olo' o? $erebell+r P=[ neuron (Purine $ell) +n" neuropil+ppe+re" 4ell preer@e" (i'ure 2/) . euron 4it! 3/>[ P 4ere e@erel"eplete" in +ll in@eti'+te" re'ion (i'ure 1, , 3, M) , $on?irmin' t!e lo o? P=[$ell. !e lo o? 3/>[ P eeme" to be more e@ere t!+n t!e lo o? P=[ neuron(i'ure 1, , 3, M) .

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1866964/figure/f1/










$oneDuen$e o? t!e lo$+l e@erit o? t!e p+t!olo'i$+l pro$e, but more liel + prim+re@ent.

lini$+ll +n" neurop+t!olo'i$+ll, $le+rl "i??er ?rom +ll ot!er !um+n *. iue p+t!olo' in ?o$ue on t!e t!+l+mu, +n" t!ere i little or no "ete$t+ble tiue

p+t!olo' in t!e $orteL. 11

*urpriin'l, !o4 onl mo"er+te (+ $omp+re" to +llot!er !um+n * in our erie) lo o? P=[ neuron +n" neuropil t+inin' in t!e ?ront+l$orteL, +ppe+rin' to be t!e onl uneDui@o$+l "i??ue p+t!olo'i$+l $!+n'e in t!e $orteL. !i mo"er+te lo o? $orti$+l P=[ neuron liel +$$ount ?or t!e li'!t tot+lneuron+l $orti$+l lo in . Ho4e@er, t!i neuron+l ubet i 4ell preer@e" in t!etempor+l $orteL +n" +"+$ent !ippo$+mpu, in triin' $ontr+t to +ll ot!er * tpe.!i +"" +not!er element to t!e eL$eption+l poition o? +mon' !um+n *. t i poible t!+t ome "i??eren$e in $lini$+l preent+tion o? , + $omp+re" 4it! ot!er*, mi'!t be "ue to t!e better preer@+tion o? P=[ $orti$+l neuron.

orti$+l but not $erebell+r P=[ neuron (Purine $ell) 7 +re ele$ti@el @ulner+ble in

*. 4o +ttribute "i$rimin+te Purine $ell ?rom +ll ot!er P=[ neuron: $oeLpreion o? +not!er $+l$ium bin"in' protein, $+lbin"in, 7 +n" l+$ o? 3/>[ P. !e?+$t t!+t P=[ neuron "e@oi" ?rom 3/>[ P u$! + Purine $ell +re uu+ll 4ell preer@e" in * +n" t!+t lo o? 3/>[ P +ppe+re" to be e@en more e@ere t!+nlo o? P=[ neuron 7,20 u''et + ?+$tor rei"in' in t!e eLtr+$ellul+r m+triL +roun"$orti$+l or !ippo$+mp+l P=[ neuron + mo"ul+tor ?or t!eir @ulner+bilit. t rem+in to beet+bli!e" !o4 $+l$ium bin"in' protein +n" t!e eLtr+$ellul+r m+triL inter+$t to $on?eru$! ele$ti@e neuron+l @ulner+bilit or reit+n$e in *, repe$ti@el.

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Acknowledgments

e t!+n epe$i+ll #r. -+me roni"e, "inbur'!, ?or +llo4in' u to ue li"e?rom t4o n@-# br+in. M. . +rner i in"l +$no4le"'e" ?or eL$ellent te$!ni$+l+it+n$e, #r. Peter /irner ?or !elpin' 4it! t+titi$, +n" #r. -o!+nne H+in?ellner ?or!elp +n" upport.

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3ootnotes

A""re reprint reDuet to #r. H. /u"+, ntitute o? eurolo', ni@erit o? =ienn+,AH 0>-, `!rin'er Grtel 18–20, PE/ >8, A1097 ien, Autri+. m+il:!.bu"+q+!4ien.+$.+t.

*upporte" b urope+n nion /iome"2 on$erte" A$tion Hum+n r+nmiible*pon'i?orm n$ep!+lop+t!ie (Prion #ie+e): europ+t!olo' +n" P!enotpi$








mailto:[email protected].







mailto:[email protected].





1>. H+in?ellner -A, 3iberi PP, Guiro #, er@en+o@+ 3, /ro4n P, G+"ue #,/u"+ H: P+t!olo' +n" immuno$to$!emitr o? + uru br+in. /r+in P+t!ol 1997,7:5>755%. IPubMe"J15. elio M: Perineuron+l net o? eLtr+$ellul+r m+triL +roun" p+r@+lbumin$ont+inin'neuron o? t!e !ippo$+mpu. Hippo$+mpu 199%, %:5560. IPubMe"J

16. /r+" #, Mu?on -: P+r@+lbuminimmunore+$ti@e neuron in t!e !ippo$+mp+l?orm+tion o? Al<!eimerX "ie+e" br+in. euro$ien$e 1997, 80:111%1125. IPubMe"J17. *olo"in A, =el"!ui<en *, =+nHoeen G: ontin'ent @ulner+bilit o? entor!in+l p+r@+lbumin$ont+inin' neuron in Al<!eimerX "ie+e. - euro$i 1996, 16:%%11%%21.IPubMe"J18. to H, Goto *, *++moto *, Hir+no A: +lbin"in#28 in t!e b++l '+n'li+ o? p+tient4it! P+rinonim. Ann eurol 1992, %2:5>%550. IPubMe"J19. Ar+i H, o'u$!i , M+ino Y, o++ , Hei<m+nn , i<u+ : P+r@+lbuminimmunore+$ti@e neuron in t!e $orteL in Pi$X "ie+e. - eurol 1991, 2%8:200202.IPubMe"J20. /eli$!eno P, Milo -, /eler /, /u"+ H, elio M: +rl "etru$tion o? t!e

eLtr+$ellul+r m+triL +roun" p+r@+lbuminimmunore+$ti@e interneurone in por+"i$ $+eo? reut<?el"t-+ob #ie+e. eurobiol #i 1999, 6:269279. IPubMe"J21. elio M: P+r@+lbumin in mot R+minobutri$ +$i"$ont+inin' neuron o? t!e r+t$erebr+l $orteL. *$ien$e 1986, 2%1:995997. IPubMe"J22. Hornun' -, ribolet : !emi$+l or'+ni<+tion o? t!e !um+n $erebr+l $orteL. r+$e #e". eurotr+nmitter in t!e Hum+n /r+in. 1995, :pp >160 Plenum Pre, e4 Yor +n"3on"on.

Jurnal B

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Epen A$$e Peere@ie4e"ee+r$! Arti$le



















&od1 "eficiency educes Incubation Time

in *ouse *odels of Prion "isease

•

*!+!een A!t+r,• -uli+ Gri<eno@+,

• A"+m enborn,

• Hol'er Hummeri$!,

• M+r ern+n"e< "e M+r$o,

• *eb+ti+n /r+n"ner,

• -o!n ollin'e,

• *+r+! . 3lo" m+il

• Arti$le• About t!e Aut!or

• Metri$

• omment

• el+te" ontent

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$itation4 A!t+r *, Gri<eno@+ -, enborn A, Hummeri$! H, ern+n"e< "e M+r$o M, et+l. (201%) *o"1 #e?i$ien$ e"u$e n$ub+tion ime in Moue Mo"el o? Prion #ie+e.P3o* E 8(1): e5>>5>. "oi:10.1%71&ourn+l.pone.005>>5>

%ditor4 -i+n M+, E!io *t+te ni@erit, nite" *t+te o? Ameri$+

ecei7ed4 o@ember 19, 2012; Accepted4 #e$ember 11, 2012; Published4 -+nu+r 22,201%

$opyright4 201% A!t+r et +l. !i i +n open+$$e +rti$le "itribute" un"er t!eterm o? t!e re+ti@e ommon Attribution 3i$ene, 4!i$! permit unretri$te" ue,"itribution, +n" repro"u$tion in +n me"ium, pro@i"e" t!e ori'in+l +ut!or +n" our$e +re$re"ite".

3unding4 !i 4or 4+ ?un"e" b t!e Me"i$+l ee+r$! oun$il (444.mr$.+$.u ).!e ?un"er !+" no role in tu" "ei'n, "+t+ $olle$tion +n" +n+li, "e$iion to publi!,

or prep+r+tion o? t!e m+nu$ript.

$ompeting interests4 - i + "ire$tor +n" !+re!ol"er o? #Gen limite", +n +$+"emi$pinout $omp+n in t!e ?iel" o? prion "i+'noi, "e$ont+min+tion +n" t!er+peuti$. !i"oe not +lter t!e +ut!orX +"!eren$e to +ll t!e P3E* Ene poli$ie on !+rin' "+t+ +n"m+teri+l.

Introduction

Prion "ie+e or tr+nmiible pon'i?orm en$ep!+lop+t!ie (*) +re pro'rei@eneuro"e'ener+ti@e "ie+e 4!i$! +re in@+ri+bl ?+t+l. !e in$lu"e reut<?el"t-+ob

"ie+e (-#) in !um+n, bo@ine pon'i?orm en$ep!+lop+t! in $+ttle (/*) +n" $r+piein !eep +n" 'o+t I1J. !e +re tr+nmiible mi?ol"e" protein "ie+e $+ue" b t!e$on@erion o? norm+l $ellul+r prion protein (PrP) to +bnorm+l io?orm, no4n + PrP*$.n +""ition to PrP*$ +$$umul+tion t!e +re $!+r+$terie" b pon'i?orm @+$uol+tion,'lioi +n" neuron+l lo in t!e br+in.

Prion "ie+e in$ub+tion time in eLperiment+l moue mo"el i rem+r+bl $onitent i?eLperiment+l p+r+meter +re ept $ont+nt, !o4e@er, t!ere i $oni"er+ble @+ri+tion bet4een "i??erent inbre" tr+in o? mi$e u''etin' + tron' 'eneti$ $ontribution. !e prion protein 'ene, Prnp, i t!e m+or $omponent 4!ere !omo<'ou no$out mi$e +re$ompletel reit+nt to prion prop+'+tion +n" "ie+e, !emi<'ou no$out mi$e !+@e +

prolon'e" in$ub+tion time +n" PrP o@ereLpreor !+@e + mu$! !orter in$ub+tion timet!+n 4il" tpe mi$e I2J, I%J. n$ub+tion time i +lo mo"ul+te" b + n+tur+ll o$$urrin' polmorp!im in Prnp 4!ere Prnp' (1083eu, 189!r) +n" Prnp- (108P!e, 189=+l)+re +o$i+te" !ort +n" lon' in$ub+tion time repe$ti@el I>J – I8J. *imil+rl, +met!ionine to @+line polmorp!im +t $o"on 129 o? !um+n PrP i +lo + m+oru$eptibilit ?+$tor ?or !um+n prion "ie+e I9J – I1%J. Mot inbre" line o? mi$e +re Prnp' +n" 4it!in t!ee t!ere i till $oni"er+ble @+ri+tion in in$ub+tion time t!uimpli$+tin' ot!er 'ene I1>J. Ou+ntit+ti@e tr+it lo$i tu" in mi$e I15J – I19J +n" 'enome

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4i"e +o$i+tion tu"ie (GA*) in !um+n I1%J, I20J u''et t!+t +lt!ou'! Prnp i t!ein'le mot import+nt ?+$tor, t!e $ombine" e??e$t o? e@er+l ot!er 'ene +re +lo o?import+n$e.

n +""ition to tr+"ition+l m+ppin' te$!niDue, in"i@i"u+l $+n"i"+te 'ene +ppro+$!e !+@e

+lo been emploe" to i"enti? 'ene t!+t in?luen$e prion "ie+e in$ub+tion time.4ent $+n"i"+te 'ene 4ere $reene" b+e" on p+t!4+ +n" 'ene pre@ioulimpli$+te" in prion "ie+e b tetin' no$out or tr+n'eni$ moue mo"el I21J. n"ert!ee $on"ition, mot 'ene !+" no e??e$t on in$ub+tion time, !o4e@er, no$out o? App (+mloi" pre$uror protein), I!16r1 (interleuin 1 re$eptor 1) +n" o@ereLpreion o?!um+n SOD1 (uperoLi"e "imut+e 1) in$re+e" ur@i@+l b 1%, 16 +n" 19Urepe$ti@el.

o tet 4!et!er App, I!16r1 +n" So01 $ontribute to t!e n+tur+ll o$$urrin' @+ri+tion ininbre" line o? mi$e 4e ue" + !etero'enou to$ (H*) o? mi$e ino$ul+te" 4it! t!e!+n"ler&o$ Mount+in 3+bor+tor (M3) moue+"+pte" $r+pie prion tr+in to loo

?or + t+titi$+l +o$i+tion bet4een prion "ie+e in$ub+tion time +n" t!ee 'eneti$ lo$iI22J – I25J. !e So01 lo$u pro"u$e" + !i'!l i'ni?i$+nt +o$i+tion t!ere?ore 4ein@eti'+te" t!i ?urt!er b $!+llen'in' So01 "e?i$ient mi$e (So01JJ) 4it! t!ree "i??erent prion tr+in.


%thics &tatement

All pro$e"ure 4ere $on"u$te" in +$$or"+n$e 4it! intitution+l, +n" intern+tion+lre'ul+tion +n" t+n"+r" on +nim+l 4el?+re +n" $on?orm to A= 'ui"eline I26J.

t!i$+l +ppro@+l 4+ 'r+nte" b t!e Me"i$+l ee+r$! oun$il (M) Prion nit et!i$$ommittee +n" $+rrie" out un"er Home E??i$e li$en$e PP370&727>.

*ice

ort!port H* mi$e (Gi?t ?rom . Hit<em+nn, Portl+n", Ere'on, *A) 4ere bre" +n" prion in$ub+tion time 4ere $olle$te" ?or mi$e +t 'ener+tion %7 (n F 1052) + pre@ioul"e$ribe" I22J. So01 no$out mi$e (/6;129*7*o"1tm13eb&-) 4ere obt+ine" ?rom t!e-+$on 3+bor+tor (/+r H+rbor, M+ine, *A) +n" b+$$roe" to 57/3&6- to Q7(Gi?t ?rom M i!er, ni@erit olle'e 3on"on ntitute o? eurolo', 3on"on, )I27J. !e reultin' !etero<'ote +nim+l (So01J) 4ere inter$roe" to pro@i"e

!omo<'ote no$out (So01JJ

) +n" 4il" tpe litter m+te $ontrol (So01

). Et!erinbre" moue line 4ere pro@i"e" b H+rl+n, 3t". (/i$eter, ).

Prion Inoculation and Phenotyping

no$ul+ 4ere m+"e ?rom t!e br+in o? termin+ll i$ mi$e + 1U (4ei'!t&@olume)!omo'en+te in #P/*. !e !+n"ler&M3 (9900), M7 (9>59) +n" M2 (9>68) prion tr+in 4ere our$e" +n" prep+re" + pre@ioul "e$ribe" I22J, I28J. Mi$e 4ere





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+n+et!eti<e" 4it! io?luor+ne&E2 +n" ino$ul+te" intr+$erebr+ll into t!e ri'!t p+riet+llobe 4it! %0 Vl o? ino$ul+ + pre@ioul "e$ribe" I15J. o minimie +nim+l u??erin',mi$e 4ere eL+mine" "+il ?or $lini$+l i'n o? prion "ie+e +n" 4ere $ulle" on$e +"e?initi@e "i+'noi !+" been m+"e or e+rlier i? !o4in' +n i'n o? "itre or ot!er!e+lt! problem. Mi$e 4ere ille" b eLpoure to $+rbon "ioLi"e '+ in riin'

$on$entr+tion. riteri+ ?or "e?inin' $r+pie in mi$e 4ere + pre@ioul "e$ribe" I29J.n$ub+tion time 4+ "e?ine" + t!e number o? "+ ?rom ino$ul+tion to "i+'noi. All pro$e"ure 4ere $on"u$te" in +$$or"+n$e 4it! intitution+l, +n" intern+tion+lre'ul+tion +n" t+n"+r" on +nim+l 4el?+re +n" $on?orm to A= 'ui"eline I26J. t!i$+l +ppro@+l 4+ 'r+nte" b t!e M Prion nit et!i$ $ommittee +n" $+rrie" outun"er Home E??i$e li$en$e PP370&727>.

P$ and &e9uencing

#A ?or e+$! o? t!e !etero'eneou to$ p+rent+l line 4+ obt+ine" ?rom t!e -+$on3+bor+tor (/+r H+rbor, M+ine, *A). P +n" eDuen$in' re+$tion 4ere $+rrie" out +

pre@ioul "e$ribe" I2%J +n" run on + %7%0 $+pill+r eDuen$er (Applie" /iotem).

Genotyping

#A 4+ eLtr+$te" ?rom t!e H* $ro mi$e + pre@ioul "e$ribe" I2%J. *P'enotpin' 4+ $+rrie" out uin' t!e Alleli$ #i$rimin+tion ?un$tion on + 7500 +te+ltime P m+$!ine (Applie" /iotem) uin' oLMe'+MiL Gol" (Mi$ro<one,3t") + pre@ioul "e$ribe" I2%J. Primer +n" probe +re !o4n in +ble *1.

eal-time T-P$

!ole br+in A 4+ eLtr+$te" ?rom unin?e$te" (6–8 4ee ol") mi$e +n" re@eretr+n$ribe" uin' AM= re@ere tr+n$ript+e +n" r+n"om primer + pre@ioul "e$ribe"I29J. ontrol re+$tion 4ere $+rrie" out 4it! no re@eretr+n$ription ?or e+$! +mple toenure no 'enomi$ #A $ont+min+tion o? t!e A prep+r+tion. e+ltime Pre+$tion 4ere $+rrie" out on + 7500 +t e+ltime P *tem (Applie" /iotem)+ pre@ioul "e$ribe" I29J. So01 +Dm+n Gene Lpreion ++ (3i?e e$!nolo'ie)4+ "upleLe" 4it! e+$! o? t!ree en"o'enou $ontrol (GAPDH , @6'#$"n +n" T/61> I2%J.All re+$tion 4ere $+rrie" out in tripli$+te. All "+t+ p+e" + norm+lit tet +n" 4+t+titi$+ll e@+lu+te" uin' + ttet.

5estern (lotting

or "ete$tion o? PrP*$ b 4etern blottin' 10U (4ei'!t&@olume) br+in !omo'en+te in #P/* 4ere prep+re" b ribolin'. *+mple 4ere ben<on+e tre+te" +n" protein+e "i'ete" (50 V'&ml o? protein+e ?or 1 ! +t %7) +n" blotte" + "e$ribe" pre@ioulI%0J. PrP 4+ "ete$te" 4it! +ntiPrP mono$lon+l +ntibo" *M%5 (#Gen 3t", )I%1J +n" +l+linep!op!+t+e$onu'+te" +ntimoue 'G e$on"+r +ntibo" (*i'm+Al"ri$!) "e@elope" in t!e $!emilumine$ent ubtr+te #P*t+r (ropiL n$). or"ete$tion o? *o"1, +mple 4ere prep+re" + +bo@e but 4it!out protein+e "i'etion



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+n" "ete$te" 4it! + r+bbit pol$lon+l +ntibo" (0.5 u'&ml) (Ab$+m). Anti+$tin mouemono$lon+l +ntibo" (0.05 u'&ml) (*i'm+) 4+ ue" + +n intern+l $ontrol + pre@ioul"e$ribe" I28J.

Immunohistochemistry

Moue br+in 4ere ?iLe" in 10U bu??ere" ?orm+l +line (/*) +n" prion in?e$te" tiue4+ tre+te" in 98U ?ormi$ +$i" ?or one !our to remo@e in?e$ti@it. iue 4ere p+r+??in4+L embe""e", e$tione" +n" t+ine" + pre@ioul "e$ribe" I29J. *e$tion 4ere t+ine"4it! !+em+toLlin +n" eoin (H) ?or 'ener+l @ie4in' in$lu"in' +ement o?pon'ioi +n" neuron+l lo. #ie+e +o$i+te" prion "epoition 4+ @iu+lie" 4it!+ntiPrP mono$lon+l +ntibo" *M%5 (#Gen 3t", ) +n" 'lioi 4+ "etermine"4it! +n +nti'li+l ?ibrill+r +$i" protein (GAP) +ntibo" (#+o 3t", ).

uantification of PrPc

10U (4ei'!t&@olume) br+in !omo'en+te 4ere ue" to me+ure en"o'enou le@el o?PrP$ b en<me line" immunoorbent ++ (3*A) + pre@ioul "e$ribe" I%2J. ot+l protein $on$entr+tion 4+ me+ure" uin' + Pier$e /A protein ++ it (!ermo*$ienti?i$) +$$or"in' to t!e m+nu?+$turerX intru$tion.

&upero8ide "ismutase %nymatic Acti7ity Assay

ot+l *E# +$ti@it 4+ me+ure" in 10U 4ei'!t&@olume (20 mM HP*, pH 7.2, 1 mMGA, 210 mM m+nnitol, 70 mM u$roe) br+in !omo'en+te uin' + *E# ++ it(+lbio$!em) +$$or"in' to t!e M+nu?+$turerX intru$tion. A oom+ie (/r+"?or") protein ++ it (/io+") 4+ ue" to me+ure t!e tot+l protein $on$entr+tion +$$or"in'

to t!e m+nu?+$turerX intru$tion.

&tatistical Analysis

*t+titi$+l tet 4ere $+rrie" out uin' Gr+p!P+" n*t+t (Gr+p!P+" *o?t4+re, n$,+li?orni+, *A) +n" *P** (/M). !e +pl+nMeier lo'r+n tet 4+ ue" to +n+leur@i@+l "+t+.

esults

Association &tudies

o loo ?or +n +o$i+tion bet4een App, I!16r1, So01 +n" prion "ie+e in$ub+tion time4e ue" t!e ort!port H* o? mi$e + pre@ioul "e$ribe" I22J, I2%J, I25J, I%%J. !eto$ 4+ 'ener+te" ?rom ei'!t p+rent+l line (A&-, A&-, /A3/&$-, %H&He-,57/3&6-, /A&-, #/A&2- +n" 3P&-) +n" n F 1052 mi$e ?rom 'ener+tion %7 4ereino$ul+te" 4it! t!e !+n"ler&M3 moue +"+pte" $r+pie prion tr+in I22J.











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•

ori'in+l im+'e (111/)

Table 1) *aHor strain distribution patterns genotyped for +& mice)

"oi:10.1%71&ourn+l.pone.005>>5>.t001

#o4nlo+":• PP

Po4erPoint li"e

• PG

l+r'er im+'e (55/)

•

ori'in+l im+'e (199/)

Table 6) &NP genotyping in +& mice)

"oi:10.1%71&ourn+l.pone.005>>5>.t002

Sod1 mNA %8pression

/+e" on t!e +o$i+tion tu" "+t+ I!16r1 +n" So01 lo$i +re +o$i+te" 4it! prion "ie+ein$ub+tion time, !o4e@er, So01 !+ t!e tron'et e??e$t 4it! + me+n "i??eren$e o? 17 "+ bet4een t!e !omo<'ou 'enotpe $omp+re" to 11 "+ ?or t!e I!16r1 'enotpe,t!ere?ore, 4e onl ?ollo4e" up t!e So01 "+t+. o no4n ?un$tion+l polmorp!im 4ere?oun" in t!e H* p+rent+l tr+in ?or So01 +n" o 4e me+ure" So01 mA eLpreionle@el in unin?e$te" br+in ?rom t!e p+rent+l line o? t!e H* (eL$ept 3P) to ee 4!et!eren"o'enou eLpreion le@el 4+ +o$i+te" 4it! 'enotpe. So01 mA eLpreionle@el 4ere Du+nti?ie" uin' re+l time P. Alt!ou'! @+ri+tion bet4een t!e inbre"line 4+ een (i'ure 1A), 4!en 'roupe" b So01 'enotpe (A F A, /A3/, %H, 57;G F A, /A, #/A) t!i 4+ not i'ni?i$+nt (i'ure 1/). e +lo +4 no "i??eren$e in

*o"1 protein eLpreion b 4etern blot bet4een A +n" G +llele mi$e eit!er in unin?e$te"or !+n"ler&M3 in?e$te" mi$e (i'ure 1–#).

#o4nlo+":• PP

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Po4erPoint li"e

• PG

l+r'er im+'e (792/)

•

ori'in+l im+'e (2.69M/)

3igure 1) Sod1 e8pression in mouse brain)

P+nel A +n" /. Ou+nti?i$+tion o? So01 mA eLpreion in 4!ole br+in b re+ltime P. F 6 ?or +ll 'roup +n" +mple 4ere run in tripli$+te. All +mple 4ere "upleLe"?or So01 (+ml+bel) +n" +n en"o'enou $ontrol GAPDH @6'#$"n or T/61 (=i$l+bel).Lpreion le@el i eLpree" in +rbitr+r unit + norm+lie" b t!e 'eometri$ me+n o?

t!e Du+ntit o? t!e en"o'enou $ontrol ( /+Li). rror b+r repreent t!e t+n"+r""e@i+tion. (A) So01 mA eLpreion le@el ?or p+rent+l tr+in o? t!e H* mi$e (eL$ept3P). (/) So01 mA eLpreion le@el 'roupe" b +llele (A&G) (A F A, /A3/, %H,57; G F A, /A, #/A). o i'ni?i$+nt "i??eren$e 4+ ober@e" bet4een t!e 'roup.P+nel () +n" (#). Ou+nti?i$+tion o? *o"1 protein in 4!ole br+in (10U !omo'en+te,4ei'!t&@olume) ?rom n F % A +llele mi$e (57/l&6) +n" G +llele mi$e (=/&). =/&mi$e 4ere ue" to repreent + G +llele tr+in r+t!er t!+n +n H* p+rent+l tr+in "ue to+@+il+bilit o? tiue. *+mple 4ere immunoblotte" 4it! r+bbit pol$lon+l +nti!um+n*E#1(Ab$+m) +n" "ete$te" 4it! #e800 ('reen) $onu'+te" 'o+t +ntir+bbit 'G(3ior). Anti+$tin moue mono$lon+l +ntibo" (*i'm+) 4+ +lo in$lu"e" + +lo+"in' $ontrol +n" 4+ "ete$te" uin' #e680 (re") $onu'+te" 'o+t +ntimoue 'G

(3ior). luore$en$e 4+ @iu+lie" uin' +n E"e in?r+re" im+'er (3ior). ()nino$ul+te" mi$e, (#) ermin+ll i$ !+n"ler&M3 prion ino$ul+te" mi$e.

"oi:10.1%71&ourn+l.pone.005>>5>.'001

Transmission of Prions to Sod1−/− *ice

t 4+ pre@ioul reporte" t!+t o@ereLpreion o? !um+n *E#1 in + tr+n'eni$ mouemo"el in$re+e" prion "ie+e in$ub+tion time 4it! t!e M3 prion tr+in, !o4e@er, t!i4+ not repli$+te" 4it! t!e %01 = (/* p++'e" in Prnp- +llele mi$e, /6.) tr+in I21J.!ee tr+nmiion 4ere $+rrie" out in m+ll 'roup (n F > or 5), on + miLe" 'eneti$

b+$'roun" +n" in t!e preen$e o? + ?orei'n protein, t!ere?ore, to $l+ri? t!e role o? *o"14e tr+nmitte" t!ree "i??erent prion tr+in to *o"1 "e?i$ient mi$e. e ue" So01 no$out mi$e /6;129*7*o"1tm13eb&- b+$$roe" to 57/3&6- (So01JJ) +n" t!eir litterm+te (So01) + 4il" tpe $ontrol I27J. Alt!ou'! mut+tion in !um+n *E#1 +re+o$i+te" 4it! ?+mili+l +motrop!i$ l+ter+l $leroi (?A3*), So01 "e?i$ient mi$e +reneurolo'i$+ll norm+l +n" "o not "e@elop pont+neou neuro"e'ener+ti@e "ie+e. !eonl p!enotpe +o$i+te" 4it! t!ee mi$e i ?em+le terilit in !omo<'ote no$outI27J. e ino$ul+te" mi$e intr+$erebr+ll 4it! t4o "i??erent moue+"+pte" $r+pie prion


http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054454.g001/largerimage


http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054454.g001/originalimage
















tr+in, !+n"ler&M3 +n" M7, +n" + moue +"+pte" /* prion tr+in, M2 (/* p++'e" in Prnp' mi$e) I28J, I%>J. n So01JJ mi$e + i'ni?i$+nt "e$re+e in in$ub+tiontime 4+ een ?or +ll t!ree prion tr+in + $omp+re" to So01 $ontrol (i'ure 2 +n"+ble *2). or !+n"ler&M3 prion t!e me+n in$ub+tion time ("+ S em) 4+ re"u$e" b 20U ?rom 156S1 in So01 to 125S1 in So01JJ mi$e (PK0.0001, +pl+nMeier lo'

r+n ur@i@+l) +n" ?or M7 t!e me+n in$ub+tion time 4+ re"u$e" b 1%U ?rom 16>S2 inSo01 to 1>2S5 in So01JJ mi$e (PK0.0001, +pl+nMeier lo' r+n ur@i@+l). or M2t!e me+n in$ub+tion time 4+ re"u$e" b 2>U ?rom 178S2 in So01 to 1%6S7 in So01J

J mi$e (PK0.0001, +pl+nMeier lo' r+n ur@i@+l). !ee "+t+ 4ere obt+ine" uin'?em+le mi$e, !o4e@er, imil+r reult 4ere +lo re$or"e" ?or m+le mi$e +lt!ou'! t!eme+n "i??eren$e 4ere re"u$e" to 16, 5 +n" 1%U ?or !+n"ler&M3, M7 +n" M2 prion tr+in repe$ti@el (+ble *2).

#o4nlo+":• PP

Po4erPoint li"e

• PG

l+r'er im+'e (112/)

•


3igure 6) /aplan-*eier sur7i7al cur7es)

#+t+ +re !o4n + U o? +nim+l (?em+le) ur@i@in' (+Li) plotte" +'+int t!e number o? "+ pot ino$ul+tion (L+Li). (A) r+nmiion o? !+n"ler&M3 prion tr+in to So01JJ

+n" So01 () litter m+te $ontrol (/) r+nmiion o? M7 prion tr+in to So01JJ +n" So01 (). () r+nmiion o? M2 moue +"+pte" /* prion tr+in to So01J

J +n" So01 (). A re"u$tion in me+n in$ub+tion time o? 20U, 1%U, +n" 2>U 4+een in A repe$ti@el. !i re"u$tion in ur@i@+l 4+ t+titi$+ll i'ni?i$+nt ?or e+$!tr+nmiion (PK0.001, +pl+nMeier lo'r+n ur@i@+l tet).

"oi:10.1%71&ourn+l.pone.005>>5>.'002

Prion tr+in $+n be "i??erenti+te" b bio$!emi$+l "i??eren$e in PrP*$ or b p+ttern o?neurop+t!olo' in re$ipient +nim+l. etern blottin' o? br+in ?rom in?e$te" +nim+l$on?irme" t!+t t!ere i no $!+n'e to t!e PrP*$ tpe $+ue" b repli$+tion in t!e +ben$e o? *o"1 (i'ure %). P+t!olo'i$+l e@+lu+tion 4+ $+rrie" out on br+in e$tion ?rom So01JJ



























• PG

l+r'er im+'e (10.11M/)

•

ori'in+l im+'e (9.>%M/)

3igure @) *' histology)

Hitolo'i$+l ?e+ture o? !+n"ler&M3 prion tr+nmiion to So01JJ (A–) +n" 4il"tpe $ontrol (#–) mi$e. P+nel A +n" # !o4 "itribution o? "ie+e+o$i+te" PrP bimmuno!ito$!emitr uin' +ntiPrP mono$lon+l +ntibo" *M%5. P+nel /, , +n" !o4 "et+il ?rom t!e !ippo$+mpu +n" +re t+ine" 4it! !+em+toLlin +n" eoin (H)to @iu+lie pon'i?orm $!+n'e +n" neuron+l lo. !ere i +lmot no neuron+l lo in t!eSo01JJ mi$e but mil" neuron+l lo i een in t!e 4il" tpe +nim+l. E@er+ll, t!e p+ttern

o? pon'ioi, 'lioi +n" PrP "itribution +re imil+r bet4een t!e t4o 'roup, !o4e@er,t!e "itribution o? "ie+e+o$i+te" PrP i p+t$!ier in t!e no$out epe$i+ll in t!e$orteL. *$+le b+r $orrepon" to % mm (A, #), 660 Vm (/, ) or 160 Vm (, ).

"oi:10.1%71&ourn+l.pone.005>>5>.'00>

e !+@e !o4n t!+t @+ri+tion +t t!e So01 lo$u i +o$i+te" 4it! prion "ie+ein$ub+tion time +n" t!+t t!i i not eLpl+ine" b "i??eren$e in mA eLpreion [email protected] t!ere?ore looe" +t *o"1 protein le@el b 4etern blot in So01 $ontrol mi$ein?e$te" 4it! !+n"ler&M3, M7 +n" M2 prion +n" $omp+re" t!ee 4it! +'em+t$!e" $ontrol (P/* ino$ul+te" mi$e). o "i??eren$e 4ere een bet4een t!e ?our

'roup (i'ure 5A). e +lo $on?irme" t!+t t!e So01JJ

mi$e ue" in t!ee eLperiment"i" not eLpre +n "ete$t+ble *o"1 protein (i'ure 5/). Alt!ou'! t!e +mount o? *o"1+ppe+r t!e +me in unin?e$te" +n" in?e$te" mi$e it i poible t!+t *o" en<me +remore +$ti@e in t!e en@ironment $re+te" b prion in?e$tion. e t!ere?ore me+ure" tot+l*o" en<m+ti$ +$ti@it in So01 mi$e in?e$te" 4it! e+$! o? t!ree prion tr+in +n"$omp+re" t!ee to unin?e$te" +nim+l. o i'ni?i$+nt "i??eren$e 4ere een bet4een t!e'roup (i'ure 5).

#o4nlo+":•

PP

Po4erPoint li"e

• PG

l+r'er im+'e (7>8/)

























•


3igure ) uantification of &od and PrP$

. 10U 4ei'!t&@olume br+in !omo'en+te immunoblotte" 4it! r+bbit pol$lon+l +nti!um+n *E#1 (Ab$+m) +n" "ete$te" 4it! #e800 ('reen) $onu'+te" 'o+t +ntir+bbit 'G (3ior). Anti+$tin moue mono$lon+l +ntibo" (*i'm+) 4+ +lo in$lu"e"+ + lo+"in' $ontrol +n" 4+ "ete$te" uin' #e680 (re") $onu'+te" 'o+t +ntimoue'G (3ior). luore$en$e 4+ @iu+lie" uin' +n E"e in?r+re" im+'er (3ior).(A) /r+in ?rom So01 4il" tpe mi$e ino$ul+te" 4it! P/* $omp+re" 4it! en" t+'e*o"1[&[ 4il" tpe mi$e ino$ul+te" 4it! M3, M7 +n" M2 prion tr+in. o"i??eren$e 4ere een bet4een t!e 'roup. (/) nin?e$te" mi$e. () ot+l *E#en<m+ti$ +$ti@it in 10U (4&@) So01 () br+in. /r+in ?rom termin+ll i$ mi$ein?e$te" 4it! M3, M7 +n" M2 4ere $omp+re" 4it! unin?e$te" mi$e. *+mple 4ere

run in tripli$+te 4it! n F 6 ?or e+$! 'roup. #+t+ +re !o4n norm+lie" b tot+l protein$ontent (V'&ml) + "etermine" b + /r+"?or" protein ++ (me+n S t+n"+r" "e@i+tion). o i'ni?i$+nt "i??eren$e 4+ een bet4een t!e 'roup. (#) PrP$ le@el in So01JJ +n"So01 () litter m+te $ontrol mi$e b 3*A. PrP$ le@el (V'&ml) 4ere "etermine" intripli$+te uin' 10U (4ei'!t&@olume) br+in !omo'en+te ?or So01JJ (n F %) +n" So01 (nF %) in + PrP pe$i?i$ 3*A I%2J. #+t+ +re !o4n norm+lie" b tot+l protein $ontent(V'&ml +n" L 1000) + "etermine" b + /A ++ (me+n S t+n"+r" "e@i+tion). oi'ni?i$+nt "i??eren$e 4+ een bet4een t!e t4o 'roup.

"oi:10.1%71&ourn+l.pone.005>>5>.'005

n eLperiment+l moue mo"el t!e le@el o? PrP

$

eLpreion !+ + pro?oun" e??e$t onin$ub+tion time t!ere?ore it i poible t!+t t!e re"u$tion in in$ub+tion time ober@e" inSo01JJ mi$e $oul" be t!e reult o? +n upre'ul+tion o? t!e en"o'enou le@el o? PrP$ I2J, I%J. e tete" t!i b me+urin' tot+l PrP$ le@el in + PrP pe$i?i$ 3*A in *o"1& +n"So01 mi$e I%2J. o i'ni?i$+nt "i??eren$e 4+ ober@e" (i'ure 5#).

"iscussion

Ou+ntit+ti@e tr+it lo$i m+ppin' in mi$e +n" GA* in !um+n !+@e $on?irme" t!+tmultiple 'ene in +""ition to Prnp in?luen$e prion "ie+e in$ub+tion time +n"u$eptibilit I1%J, I15J, I17J, I18J, I20J. !ee tu"ie !+@e u$$e?ull i"enti?ie"

$+n"i"+te lo$i but no in"i@i"u+l 'ene !+@e et been $on?irme" + ?un$tion+lli'ni?i$+nt. Altern+ti@e tr+te'ie !+@e in$lu"e" t+r'etin' 'ene ?rom p+t!4+impli$+te" in prion "ie+e +n" tetin' t!em "ire$tl in moue mo"el. !i i"enti?ie" App, I!16r1 +n" So01 + interetin' $+n"i"+te, !o4e@er, it "i" not +""re 4!et!er or nott!e $ontribute" to t!e n+tur+l @+ri+tion I21J. n t!i tu" 4e $+rrie" out +n +o$i+tiontu" ?or e+$! o? t!ee 'ene in H* o? mi$e. !e m+ppin' reolution +@+il+ble in t!e H*$ro +t 'ener+tion %7 i +pproLim+tel 1–2 $M 4!i$! i too bi' to un+mbi'uoul












http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Stephenson1

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Manolakou1













http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Stephenson1

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Manolakou1





+$ribe +n +o$i+tion to one 'ene +lt!ou'! m+ppin' to *#P m+ !elp to n+rro4 "o4nt!e re'ion I25J.

App i + @er promiin' $+n"i"+te 'ene p+rti$ul+rl 'i@en it in@ol@ement in Al<!eimerX"ie+e (A#), + neuro"e'ener+ti@e protein mi?ol"in' "ie+e. !ere i +lo in$re+in'

e@i"en$e ?or +n inter+$tion 4it! PrP 4!ere PrP !+ been impli$+te" in pottr+nl+tion+l pro$ein' o? APP t!rou'! t!e in!ibition o? /A1 +n" in ome moue mo"el PrP m+ bin" +mloi" +n" me"i+te +pe$t o? it neurotoLi$it I%5J – I%8J. #epite it +ttr+$tion+ + $+n"i"+te 4e "i" not ?in" +n e@i"en$e o? +n +o$i+tion 4it! prion "ie+ein$ub+tion time in t!i $ro +lt!ou'! it i poible t!+t ot!er *#P not tete" b u m+!o4 ome +o$i+tion. App m+ till !+@e + role in prion "ie+e +lt!ou'! it "oe not+ppe+r to $ontribute to t!e n+tur+l @+ri+tion ober@e" in t!e p+rent+l line o? t!i $ro.

l1r1 i + re$eptor ?or t!e proin?l+mm+tor $toine, l1, pro"u$e" b 'li+ +n"impli$+te" in t!e "ie+e pro$e + + reult o? eLteni@e 'lioi. I!16r1 no$out mi$e!+@e been pre@ioul tu"ie" $on?irmin' t!+t "eletion o? I!16r1 i prote$ti@e in mo"el o?

moue $r+pie I21J, I%9J. n t!i tu" 4e i"enti? + nonnonmou *P (Al+71=+l) on+ *#P t!+t i line" to prion "ie+e in$ub+tion time. t i not $le+r 4!et!er t!i *P it!e ?un$tion+l @+ri+nt or 4!et!er it i $+rrie" 4it!in t!e +me !+plotpe blo$.

*o"1 i +n ubiDuitoul eLpree" $topl+mi$ uperoLi"e "imut+e t!+t prote$t $ell?rom oLi"+ti@e "+m+'e b remo@in' uperoLi"e t!rou'! $on@ertin' it to !"ro'en peroLi"e. t !+ been +o$i+te" 4it! ot!er neuro"e'ener+ti@e "ie+e not+bl+motrop!i$ l+ter+l $leroi 4!ere mut+tion in !um+n *E#1 +$$ount ?or v20U o??+mili+l A3* $+e prob+bl @i+ + toLi$ '+in o? ?un$tion I>0J. *o"1 !+ +lo beenimpli$+te" in Al<!eimerX "ie+e 4!ereb So01 no$out +$$eler+te" +mloi"oli'omeri+tion +n" memor lo in +n A# moue mo"el +n" $on@erel o@ereLpreion

o? *o"1 re$ue t!e $erebr+l en"ot!eli+l "?un$tion in +not!er A# mo"el I>1J, I>2J. nt!i tu" 4e !+@e !o4n + !i'!l i'ni?i$+nt +o$i+tion 4it! t!e So01 lo$u +n" prion"ie+e in$ub+tion time t!ereb $on?irmin' it e??e$t on t!e n+tur+l @+ri+tion 4it!in t!eeinbre" line o? mi$e. !e ?un$tion+l *P rem+in unno4n +n" 4e !+@e not "ete$te" +ne@i"en$e ?or "i??erenti+l mA or protein eLpreion. e !+@e +lo $on?irme" t!e role o? *o"1 + + prote$ti@e ?+$tor in prion "ie+e + "eletion o? *o"1 i'ni?i$+ntl re"u$ein$ub+tion time in t4o "i??erent tr+in o? moue +"+pte" $r+pie (!+n"ler&M3 +n"M7) +n" + moue p++'e" /* prion tr+in, M2. !ee "+t+ bro+"l +'ree 4it! pre@ioul publi!e" "+t+ t!+t u''ete" + prote$ti@e e??e$t o? o@ereLprein' !um+n*E#1 in mi$e $!+llen'e" 4it! M3 but not %01 = prion I21J. !i "i??eren$e m+ beeLpl+ine" b t!e preen$e o? t!e !um+n protein or b "i??eren$e in t!e moue +"+pte"/* tr+in $+ue" b p++'e in Prnp- r+t!er t!+n Prnp' mi$e. e $+nnot eL$lu"e t!e poibilit t!+t t!e t+r'ete" no$out o? *o"1 in t!ee mi$e m+ in+"@ertentl +??e$t t!eeLpreion o? +"+$ent lo$i 4!i$! t!emel@e in?luen$e prion "ie+e in$ub+tion time +n"t!+t t!i 4oul" eLpl+in t!e +ben$e o? "ete$t+ble "i??eren$e in *o"1 eLpreion.

ELi"+ti@e tre !+ been impli$+te" in neuro"e'ener+ti@e "ie+e +n" i $+ue" beL$e re+$ti@e oL'en pe$ie u$! + uperoLi"e +$$umul+tin' 4it! t!e $ell 4!i$! m+ be t!e reult o? eL$e pro"u$tion b m+l?un$tionin' mito$!on"ri+ +n" "epletion o?



http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Parkin1

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Freir1



http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Schultz1


http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Joyce1

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Murakami1


http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Iadecola1




http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Parkin1

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Freir1



http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Joyce1






$+t+lti$ en<me. n moue mo"el o? prion "ie+e "+m+'e" mito$!on"ri+ !+@e been"e$ribe" + 4ell + e@i"en$e ?or in$re+e" uperoLi"e 'ener+tion +n" ?ree r+"i$+l"+m+'e I>%J, I>>J. M+rer o? oLi"+ti@e "+m+'e !+@e +lo been "e$ribe" in -# br+inI>5J. e "i" not "ete$t + $!+n'e in *o"1 protein eLpreion or tot+l *o" +$ti@it inrepone to prion in?e$tion 4it! +n o? our prion tr+in, !o4e@er, t!e preen$e o? norm+l

*o"1 +$ti@it i $le+rl prote$ti@e + *o"1 "e?i$ient mi$e !o4 + i'ni?i$+ntl re"u$e"in$ub+tion time +$ro +ll prion tr+in tete".

$onclusion

n $on$luion, 4e !+@e !o4n t!+t bot! I!16r1 +n" So0 but not App +re +o$i+te" 4it!t!e n+tur+l @+ri+tion in prion "ie+e in$ub+tion time me+ure" in t!e ort!port H* mi$e.n +""ition, *o"1 "e?i$ient mi$e !o4 !i'!l i'ni?i$+nt re"u$tion in in$ub+tion time o?20, 1% +n" 2>U 4it! !+n"ler&M3, M7 +n" M2 prion tr+in, [email protected]!ou'! no "i??eren$e in *o"1 eLpreion or +$ti@it 4ere "ete$te" our "+t+ !i'!li'!tt!e import+n$e o? oLi"+ti@e "+m+'e in prion "ie+e +n" t!e prote$ti@e role pl+e" b

en"o'enou *o"1 protein.

&upporting Information

i'ureT*1.ti?

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Lee1


http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Siskova1


http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Freixes1



http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054454#pone.0054454-Freixes1





• 1 & 2

•

•

•

?i' share

"o4nlo+"

*% histology) Hitolo'i$+l ?e+ture o? M7 prion tr+nmiion to So01JJ (A–) +n"4il" tpe $ontrol (#–) mi$e. P+nel A +n" # !o4 PrP*$ "itribution b t+inin' 4it!+ntiPrP mono$lon+l +ntibo" *M%5. P+nel /, , +n" !o4 "et+il ?rom t!e!ippo$+mpu +n" +re t+ine" 4it! !+em+toLlin +n" eoin (H) to @iu+liepon'i?orm $!+n'e +n" neuron+l lo. o "i??eren$e +re een bet4een t!e t4o 'roup.*$+le b+r $orrepon" to % mm (A, #), 660 Vm (/, ) or 160 Vm (, ).

3igure &1)

*% histology) Hitolo'i$+l ?e+ture o? M7 prion tr+nmiion to So01JJ (A–) +n"4il" tpe $ontrol (#–) mi$e. P+nel A +n" # !o4 PrP*$ "itribution b t+inin' 4it!+ntiPrP mono$lon+l +ntibo" *M%5. P+nel /, , +n" !o4 "et+il ?rom t!e!ippo$+mpu +n" +re t+ine" 4it! !+em+toLlin +n" eoin (H) to @iu+liepon'i?orm $!+n'e +n" neuron+l lo. o "i??eren$e +re een bet4een t!e t4o 'roup.*$+le b+r $orrepon" to % mm (A, #), 660 Vm (/, ) or 160 Vm (, ).

"oi:10.1%71&ourn+l.pone.005>>5>.001

()

3igure &6)

*$6 histology) Hitolo'i$+l ?e+ture o? M2 prion tr+nmiion to So01JJ (A–)+n" 4il" tpe $ontrol (#–) mi$e. P+nel A +n" # !o4 PrP*$ "itribution b t+inin'4it! +ntiPrP mono$lon+l +ntibo" *M%5. P+nel /, , +n" !o4 "et+il ?rom t!e!ippo$+mpu +n" +re t+ine" 4it! !+em+toLlin +n" eoin (H) to @iu+liepon'i?orm $!+n'e +n" neuron+l lo. So01JJ mi$e (#) !o4 + re"u$tion in PrP intenitrel+ti@e to 4il" tpe mi$e epe$i+ll in t!e $orteL tripe. *$+le b+r $orrepon" to % mm

(A, #), 660 Vm (/, ) or 160 Vm (, ).

"oi:10.1%71&ourn+l.pone.005>>5>.002

()

Acknowledgments

http://figshare.com/articles/Sod1_Deficiency_Reduces_Incubation_Time_in_Mouse_Models_of_Prion_Disease__/154007


http://void%280%29/

http://www.plosone.org/article/fetchSingleRepresentation.action?uri=info:doi/10.1371/journal.pone.0054454.s001



http://void%280%29/





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http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AAsante+%22BSE+prions+propagate+as+either+variant+CJD-like+or+sporadic+CJD-like+prion+strains+in+transgenic+mice+expressing+human+prion+protein%22

http://dx.doi.org/10.1093/brain/awl076



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Wadsworth%5Bauthor%5D+AND+Phenotypic+heterogeneity+in+inherited+prion+disease+(P102L)+is+associated+with+differential+propagation+of+protease-resistant+wild-type+and+mutant+prion+protein

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AWadsworth+%22Phenotypic+heterogeneity+in+inherited+prion+disease+(P102L)+is+associated+with+differential+propagation+of+protease-resistant+wild-type+and+mutant+prion+protein%22

http://www.crossref.org/guestquery/?auth2=Hitzemann&atitle2=Further-Studies+on+the+Relationship+Between+Dopamine+Cell-Density+and+Haloperidol-Induced+Catalepsy&auth=Hitzemann&atitle=Further-Studies+on+the+Relationship+Between+Dopamine+Cell-Density+and+Haloperidol-Induced+Catalepsy

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hitzemann%5Bauthor%5D+AND+Further-Studies+on+the+Relationship+Between+Dopamine+Cell-Density+and+Haloperidol-Induced+Catalepsy

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AHitzemann+%22Further-Studies+on+the+Relationship+Between+Dopamine+Cell-Density+and+Haloperidol-Induced+Catalepsy%22

http://dx.doi.org/10.1099/vir.0.79889-0


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lloyd%5Bauthor%5D+AND+Characterization+of+two+distinct+prion+strains+derived+from+bovine+spongiform+encephalopathy+transmissions+to+inbred+mice

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3ALloyd+%22Characterization+of+two+distinct+prion+strains+derived+from+bovine+spongiform+encephalopathy+transmissions+to+inbred+mice%22



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Grizenkova%5Bauthor%5D+AND+Overexpression+of+the+Hspa13+(Stch)+gene+reduces+prion+disease+incubation+time+in+mice

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AGrizenkova+%22Overexpression+of+the+Hspa13+(Stch)+gene+reduces+prion+disease+incubation+time+in+mice%22



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=O%E2%80%99Shea%5Bauthor%5D+AND+Investigation+of+Mcp1+as+a+Quantitative+Trait+Gene+for+Prion+Disease+Incubation+Time+in+Mouse

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AO%E2%80%99Shea+%22Investigation+of+Mcp1+as+a+Quantitative+Trait+Gene+for+Prion+Disease+Incubation+Time+in+Mouse%22

http://dx.doi.org/10.1016/S0140-6736(01)05403-4

http://dx.doi.org/10.1016/S0140-6736(01)05403-4

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Wadsworth%5Bauthor%5D+AND+Tissue+distribution+of+protease+resistant+prion+protein+in+variant+CJD+using+a+highly+sensitive+immuno-blotting+assay

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AWadsworth+%22Tissue+distribution+of+protease+resistant+prion+protein+in+variant+CJD+using+a+highly+sensitive+immuno-blotting+assay%22



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Asante%5Bauthor%5D+AND+BSE+prions+propagate+as+either+variant+CJD-like+or+sporadic+CJD-like+prion+strains+in+transgenic+mice+expressing+human+prion+protein

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AAsante+%22BSE+prions+propagate+as+either+variant+CJD-like+or+sporadic+CJD-like+prion+strains+in+transgenic+mice+expressing+human+prion+protein%22



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Wadsworth%5Bauthor%5D+AND+Phenotypic+heterogeneity+in+inherited+prion+disease+(P102L)+is+associated+with+differential+propagation+of+protease-resistant+wild-type+and+mutant+prion+protein

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AWadsworth+%22Phenotypic+heterogeneity+in+inherited+prion+disease+(P102L)+is+associated+with+differential+propagation+of+protease-resistant+wild-type+and+mutant+prion+protein%22

http://www.crossref.org/guestquery/?auth2=Hitzemann&atitle2=Further-Studies+on+the+Relationship+Between+Dopamine+Cell-Density+and+Haloperidol-Induced+Catalepsy&auth=Hitzemann&atitle=Further-Studies+on+the+Relationship+Between+Dopamine+Cell-Density+and+Haloperidol-Induced+Catalepsy

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hitzemann%5Bauthor%5D+AND+Further-Studies+on+the+Relationship+Between+Dopamine+Cell-Density+and+Haloperidol-Induced+Catalepsy

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AHitzemann+%22Further-Studies+on+the+Relationship+Between+Dopamine+Cell-Density+and+Haloperidol-Induced+Catalepsy%22



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lloyd%5Bauthor%5D+AND+Characterization+of+two+distinct+prion+strains+derived+from+bovine+spongiform+encephalopathy+transmissions+to+inbred+mice

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3ALloyd+%22Characterization+of+two+distinct+prion+strains+derived+from+bovine+spongiform+encephalopathy+transmissions+to+inbred+mice%22



35.%5. P+rin , +tt , Hu+in , $m+n A, $m+n /, et +l. (2007)ellul+r prion protein re'ul+te bet+e$ret+e $le+@+'e o? t!e Al<!eimerX+mloi" pre$uror protein. Pro$ +tl A$+" *$i *A 10>: 11062–11067. "oi:10.107%&pn+.060962110>.

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40.>0. -o$e P, r+tt+ P, i!er M, A$e@e"oAro<en+ A (2011) *E#1 +n" #P>% +nim+l mo"el o? +motrop!i$ l+ter+l $leroi: re$ent +"@+n$e inun"ert+n"in' "ie+e to4+r" t!e "e@elopment o? $lini$+l tre+tment. M+mmGenome 22: >20–>>8. "oi: 10.1007&00%%50119%%91.

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41.>1. Mur++mi , Mur+t+ , o"+ Y, +!+r+ *, +neo , et +l. (2011) *E#1(opper&in$ *uperoLi"e #imut+e) #e?i$ien$ #ri@e Amloi" bet+ ProteinEli'omeri<+tion +n" Memor 3o in Moue Mo"el o? Al<!eimer #ie+e. - /iol!em 286: >>557–>>568. "oi: 10.107>&b$.M111.279208.

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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Parkin%5Bauthor%5D+AND+Cellular+prion+protein+regulates+beta-secretase+cleavage+of+the+Alzheimer%E2%80%99s+amyloid+precursor+protein

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AParkin+%22Cellular+prion+protein+regulates+beta-secretase+cleavage+of+the+Alzheimer%E2%80%99s+amyloid+precursor+protein%22

http://dx.doi.org/10.1038/nature07761


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lauren%5Bauthor%5D+AND+Cellular+prion+protein+mediates+impairment+of+synaptic+plasticity+by+amyloid-beta+oligomers

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3ALauren+%22Cellular+prion+protein+mediates+impairment+of+synaptic+plasticity+by+amyloid-beta+oligomers%22

http://dx.doi.org/10.1523/JNEUROSCI.6500-10.2011



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Barry%5Bauthor%5D+AND+Alzheimer%E2%80%99s+Disease+Brain-Derived+Amyloid-beta-Mediated+Inhibition+of+LTP+In+Vivo+Is+Prevented+by+Immunotargeting+Cellular+Prion+Protein

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3ABarry+%22Alzheimer%E2%80%99s+Disease+Brain-Derived+Amyloid-beta-Mediated+Inhibition+of+LTP+In+Vivo+Is+Prevented+by+Immunotargeting+Cellular+Prion+Protein%22

http://dx.doi.org/10.1038/ncomms1341


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Freir%5Bauthor%5D+AND+Interaction+between+prion+protein+and+toxic+amyloid+beta+assemblies+can+be+therapeutically+targeted+at+multiple+sites

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AFreir+%22Interaction+between+prion+protein+and+toxic+amyloid+beta+assemblies+can+be+therapeutically+targeted+at+multiple+sites%22

http://dx.doi.org/10.1016/S0002-9440(10)63331-7

http://dx.doi.org/10.1016/S0002-9440(10)63331-7

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Schultz%5Bauthor%5D+AND+Role+of+interleukin-1+in+prion+disease-associated+astrocyte+activation

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3ASchultz+%22Role+of+interleukin-1+in+prion+disease-associated+astrocyte+activation%22

http://dx.doi.org/10.1007/s00335-011-9339-1

http://dx.doi.org/10.1007/s00335-011-9339-1

http://dx.doi.org/10.1007/s00335-011-9339-1

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Joyce%5Bauthor%5D+AND+SOD1+and+TDP-43+animal+models+of+amyotrophic+lateral+sclerosis%3A+recent+advances+in+understanding+disease+toward+the+development+of+clinical+treatments

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AJoyce+%22SOD1+and+TDP-43+animal+models+of+amyotrophic+lateral+sclerosis%3A+recent+advances+in+understanding+disease+toward+the+development+of+clinical+treatments%22

http://dx.doi.org/10.1074/jbc.M111.279208


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Murakami%5Bauthor%5D+AND+SOD1+(Copper%2FZinc+Superoxide+Dismutase)+Deficiency+Drives+Amyloid+beta+Protein+Oligomerization+and+Memory+Loss+in+Mouse+Model+of+Alzheimer+Disease



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Parkin%5Bauthor%5D+AND+Cellular+prion+protein+regulates+beta-secretase+cleavage+of+the+Alzheimer%E2%80%99s+amyloid+precursor+protein

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AParkin+%22Cellular+prion+protein+regulates+beta-secretase+cleavage+of+the+Alzheimer%E2%80%99s+amyloid+precursor+protein%22



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lauren%5Bauthor%5D+AND+Cellular+prion+protein+mediates+impairment+of+synaptic+plasticity+by+amyloid-beta+oligomers

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3ALauren+%22Cellular+prion+protein+mediates+impairment+of+synaptic+plasticity+by+amyloid-beta+oligomers%22



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Barry%5Bauthor%5D+AND+Alzheimer%E2%80%99s+Disease+Brain-Derived+Amyloid-beta-Mediated+Inhibition+of+LTP+In+Vivo+Is+Prevented+by+Immunotargeting+Cellular+Prion+Protein

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3ABarry+%22Alzheimer%E2%80%99s+Disease+Brain-Derived+Amyloid-beta-Mediated+Inhibition+of+LTP+In+Vivo+Is+Prevented+by+Immunotargeting+Cellular+Prion+Protein%22



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Freir%5Bauthor%5D+AND+Interaction+between+prion+protein+and+toxic+amyloid+beta+assemblies+can+be+therapeutically+targeted+at+multiple+sites

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AFreir+%22Interaction+between+prion+protein+and+toxic+amyloid+beta+assemblies+can+be+therapeutically+targeted+at+multiple+sites%22

http://dx.doi.org/10.1016/S0002-9440(10)63331-7

http://dx.doi.org/10.1016/S0002-9440(10)63331-7

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Schultz%5Bauthor%5D+AND+Role+of+interleukin-1+in+prion+disease-associated+astrocyte+activation

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3ASchultz+%22Role+of+interleukin-1+in+prion+disease-associated+astrocyte+activation%22

http://dx.doi.org/10.1007/s00335-011-9339-1

http://dx.doi.org/10.1007/s00335-011-9339-1

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Joyce%5Bauthor%5D+AND+SOD1+and+TDP-43+animal+models+of+amyotrophic+lateral+sclerosis%3A+recent+advances+in+understanding+disease+toward+the+development+of+clinical+treatments

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AJoyce+%22SOD1+and+TDP-43+animal+models+of+amyotrophic+lateral+sclerosis%3A+recent+advances+in+understanding+disease+toward+the+development+of+clinical+treatments%22



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Murakami%5Bauthor%5D+AND+SOD1+(Copper%2FZinc+Superoxide+Dismutase)+Deficiency+Drives+Amyloid+beta+Protein+Oligomerization+and+Memory+Loss+in+Mouse+Model+of+Alzheimer+Disease



o Goo'le *$!ol+r

>2. >2. +"e$ol+ , !+n' , i4+ , $m+n , urner *, et +l. (1999) *E#1re$ue $erebr+l en"ot!eli+l "?un$tion in mi$e o@ereLprein' +mloi" pre$uror protein. +t euro$i 2: 157–161.

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43.>%. 3ee #, *o!n HE, 3im H/, 3ee YG, im Y*, et +l. (1999) Alter+tion o? ?reer+"i$+l met+bolim in t!e br+in o? mi$e in?e$te" 4it! $r+pie +'ent. ree +"i$e %0: >99–507. "oi: 10.1080&10715769900%005>1.

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44.>>. *io@+ , M+!+" #-, Pu"ne , +mpbell G, +"o'+n M, et +l. (2010)Morp!olo'i$+l +n" un$tion+l Abnorm+litie in Mito$!on"ri+ Ao$i+te" 4it!*n+pti$ #e'ener+tion in Prion #ie+e. Am - P+t!ol 177: 1>11–1>21. "oi:

10.2%5%&+p+t!.2010.0910%7.o roe?

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45.>5. reiLe M, o"ri'ue< A, #+l?o , errer (2005) ELi"+tion, 'l$oLi"+tion,lipoLi"+tion, nitr+tion, +n" repone to oLi"+ti@e tre in t!e $erebr+l $orteL inreut<?el"t-+ob "ie+e. eurobiol A'in' 27: 1807–1815. "oi:10.1016&.neurobiol+'in'.2005.10.006.

Jurnal

urr Genomi$. 2012 Au'ut; 1%(5): %69–%78.

Publi!e" online 2012 Au'ut. "oi: 10.217>&1%892021280161922%PM#: PM%>0189>

3unctional Genomics Approach for

Identification of *olecular Processes

#nderlying Neurodegenerati7e "isorders

in Prion "iseases

rmil+ /+u,1,B 3e 3uo Gu+n,1 +n" *tep!en * Moore2

Aut!or in?orm+tion C Arti$le note C opri'!t +n" 3i$ene in?orm+tion CGo to:

Abstract

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AMurakami+%22SOD1+(Copper%2FZinc+Superoxide+Dismutase)+Deficiency+Drives+Amyloid+beta+Protein+Oligomerization+and+Memory+Loss+in+Mouse+Model+of+Alzheimer+Disease%22

http://www.crossref.org/guestquery/?auth2=Iadecola&atitle2=SOD1+rescues+cerebral+endothelial+dysfunction+in+mice+overexpressing+amyloid+precursor+protein&auth=Iadecola&atitle=SOD1+rescues+cerebral+endothelial+dysfunction+in+mice+overexpressing+amyloid+precursor+protein

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Iadecola%5Bauthor%5D+AND+SOD1+rescues+cerebral+endothelial+dysfunction+in+mice+overexpressing+amyloid+precursor+protein

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AIadecola+%22SOD1+rescues+cerebral+endothelial+dysfunction+in+mice+overexpressing+amyloid+precursor+protein%22

http://dx.doi.org/10.1080/10715769900300541

http://dx.doi.org/10.1080/10715769900300541

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lee%5Bauthor%5D+AND+Alteration+of+free+radical+metabolism+in+the+brain+of+mice+infected+with+scrapie+agent

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3ALee+%22Alteration+of+free+radical+metabolism+in+the+brain+of+mice+infected+with+scrapie+agent%22

http://dx.doi.org/10.2353/ajpath.2010.091037


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Siskova%5Bauthor%5D+AND+Morphological+and+Functional+Abnormalities+in+Mitochondria+Associated+with+Synaptic+Degeneration+in+Prion+Disease

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3ASiskova+%22Morphological+and+Functional+Abnormalities+in+Mitochondria+Associated+with+Synaptic+Degeneration+in+Prion+Disease%22

http://dx.doi.org/10.1016/j.neurobiolaging.2005.10.006

http://dx.doi.org/10.2174%2F138920212801619223

http://www.ncbi.nlm.nih.gov/pubmed/?term=Basu%20U%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Guan%20LL%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Moore%20SS%5Bauth%5D







http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AMurakami+%22SOD1+(Copper%2FZinc+Superoxide+Dismutase)+Deficiency+Drives+Amyloid+beta+Protein+Oligomerization+and+Memory+Loss+in+Mouse+Model+of+Alzheimer+Disease%22

http://www.crossref.org/guestquery/?auth2=Iadecola&atitle2=SOD1+rescues+cerebral+endothelial+dysfunction+in+mice+overexpressing+amyloid+precursor+protein&auth=Iadecola&atitle=SOD1+rescues+cerebral+endothelial+dysfunction+in+mice+overexpressing+amyloid+precursor+protein

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Iadecola%5Bauthor%5D+AND+SOD1+rescues+cerebral+endothelial+dysfunction+in+mice+overexpressing+amyloid+precursor+protein

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3AIadecola+%22SOD1+rescues+cerebral+endothelial+dysfunction+in+mice+overexpressing+amyloid+precursor+protein%22

http://dx.doi.org/10.1080/10715769900300541

http://dx.doi.org/10.1080/10715769900300541

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lee%5Bauthor%5D+AND+Alteration+of+free+radical+metabolism+in+the+brain+of+mice+infected+with+scrapie+agent

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3ALee+%22Alteration+of+free+radical+metabolism+in+the+brain+of+mice+infected+with+scrapie+agent%22



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Siskova%5Bauthor%5D+AND+Morphological+and+Functional+Abnormalities+in+Mitochondria+Associated+with+Synaptic+Degeneration+in+Prion+Disease

http://scholar.google.com/scholar?hl=en&safe=off&q=author%3ASiskova+%22Morphological+and+Functional+Abnormalities+in+Mitochondria+Associated+with+Synaptic+Degeneration+in+Prion+Disease%22

http://dx.doi.org/10.1016/j.neurobiolaging.2005.10.006

http://dx.doi.org/10.2174%2F138920212801619223

http://www.ncbi.nlm.nih.gov/pubmed/?term=Basu%20U%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Guan%20LL%5Bauth%5D










+ble 1.r+nmiible *pon'i?orm n$ep!+lop+t!ie (Prion #ie+e) in Hum+n +n" Anim+l

n'etion o? $ont+min+te" biolo'i$+l m+teri+l @i+ ?oo" reulte" in t!e +$Duire" ?orm o?"ie+e e.'., uru 4+ t!e ?irt no4n !um+n * "ue to ritu+liti$ $+nnib+lim I5J.

/* i +not!er m+i@e $ommonour$e epi"emi$ $+ue" b me+t +n" bone me+l ?e" prim+ril to "+ir $o4 I6, 7J +n" more re$entl @-# in !um+n !+ been +o$i+te" 4it!eLpoure to t!e /* +'ent I1J. En t!e ot!er !+n", mut+tion in t!e norm+l prion proteinen$o"e" b t!e Pio Protein (PP) 'ene, +re line" to 'eneti$+ll in!erite" prion"ie+e in$lu"in' Gertm+nn*tr+uler*!einer (G**) "ie+e, ?+t+l ?+mili+l inomni+() +n" 'eneti$+ll +o$i+te" -# I2, >J.

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6)PAT+!G%N%&I& !3 PI!N "I&%A&%

n m+mm+l, t!e $on@erion o? t!e norm+l, $ellul+r io?orm o? t!e prion protein (PrP) tot!e "ie+e$+uin' io?orm (PrP*$) i t!e e pro$e un"erlin' prion "ie+e. PrP +n"PrP*$ !+@e "itin$t $on?orm+tion 4it! PrP !+ eLteni@e w!eli$+l $ontent 4!ere+ PrP*$

i ri$! in !eet tru$ture 4it! le w!eli$+l $ontent I8, 9J, !+ t!e propenit to+''re'+te +n" !+ t!e reit+n$e to proteoli I10J. Prion "ie+e in +nim+l $+n be$!+r+$teri<e" b PrP*$ repli$+tion +n" +$$umul+tion, pon'i?orm @+$uol+tion +n"+tro$ti$ 'lioi, n+pti$ "e'ener+tion le+"in' to neuro"e'ener+tion +n" let!+lit I11J4!ile t!ee mptom +re $ommon in m+n neuro"e'ener+ti@e "ior"er I5, 12J.ApproLim+tel >5U o? t!e PrP protein i w!eli$+l 4it! t4o @er !ort tret$!e o? !eet +n" it $on@erion to PrP*$ reult in protein 4it! v%0U w!eliL +n" >5U !eet.Et!er +n$ill+r protein +re +lo in@ol@e" in t!i $on@erion pro$e +n" PrP$ +ppe+r to

bin" to PrP*$ to ?orm +n interme"i+te $ompleL I1%J. !e m+or route o? tr+nmiion ?orm+n * i t!rou'! or+l in?e$tion +?ter 4!i$! prion pre+" t!rou'! t!e 'ut toe$on"+r immune tiue +n" t!en to t!e br+in I5J. urt!ermore, prion !+@e been"ete$te" in "i??erent lmp!oi" or'+n in$lu"in' t!e pleen, lmp! no"e, PeerX p+t$!e+n" tonil I1>16J.

Prion protein (PrP) i en$o"e" b + $!romoom+l 'ene, PRNP 4it! + in'le eLon ?or t!ePrP open re+"in' ?r+me +lt!ou'! t!e 'ene itel? $omprie o? t4o to t!ree eLon I1720J.!e ot!er eLon o? t!e PP 'ene $ont+in untr+nl+te" eDuen$e in$lu"in' t!e promoter +n" termin+tion ite 4it! multiple $opie o? Gri$! repe+t in t!e PrP promoter I21J.omp+rion o? + tot+l o? 9%7 PRNP eDuen$e ?rom 8% pe$ie u''ete" + triin'

"e'ree o? $oner@+tion +mon' t!e m+mm+li+n eDuen$e I22J. Ho4e@er, @+ri+tion inPrP eDuen$e eLit bot! bet4een pe$ie +n" bet4een in"i@i"u+l 4it!in pe$ie 're+tl+??e$tin' u$eptibilit to prion in?e$tion I2%J. n$re+in' e@i"en$e u''et t!+t ot!er'ene in +""ition to t!e PP 'ene +lo $ontribute to t!e 'eneti$ u$eptibilit o?+$Duire" *, t!u t!ere i + nee" to impro@e our un"ert+n"in' o? t!e mole$ul+rme$!+nim un"erlin' prion "ie+e p+t!o'enei. Genome4i"e tu"ie in $+ttle I2>28J, !eep I29, %0J, mi$e I%1, %2J, +n" !um+n I%%J !+@e i"enti?ie" 'enomi$ re'ion +n" poition+l $+n"i"+te 'ene, ot!er t!+n t!e prion 'ene, in@ol@e" in * p+t!o'enei. !i


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401894/#R5
































































re@ie4 !i'!li'!t t!e re$ent +"@+n$e in t!e ?iel" o? prion "ie+e in !um+n, mouemo"el +n" rumin+nt pe$ie to un"ert+n" t!e $ompleLitie o? mole$ul+r p+t!4+ uin'!i'! t!rou'!put ?un$tion+l 'enomi$ te$!nolo'ie.

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;)+IG+ T+!#GP#T G%N% %P%&&I!N

&T#"I%& A&&!$IAT%" 5IT+ +#*AN PI!N

"I&%A&%&

!e PRNP 'ene "etermine bot! u$eptibilit +n" p!enotpe o? prion "ie+e in!um+n, 4it! point mut+tion le+"in' to + pe$i?i$ p+t!olo'i$+l p!enotpe I%>, %5J. A'enome4i"e tu" in p+tient 4it! @+riou ?orm o? prion "ie+e (@+ri+nt, por+"i$,i+tro'eni$ -# +n" uru p+tient) $on?irme" t!+t t!e ri o? "e@elopin' prion "ie+e itron'l +o$i+te" 4it! t!e polmorp!i$ $o"on 129 o? t!e PRNP 'ene I%%J. Preen$e o?

in'le nu$leoti"e polmorp!im (*P) in t!e intron o? PRNP , retinoi$ +$i" re$eptor protein =RARB>, +n" *G10&t+t!minlie 2, + neuron+l 'ro4t!+o$i+te" protein(STMN2) in$re+e" t!e ri o? prion "ie+e. etinoi$ +$i" i no4n to re'ul+te t!eeLpreion o? t!e prion protein in $ell $ulture I%6J, +n" *G10 mo"ul+te mi$rotubulet+bilit in neuron+l $ell, 4!i$!, in turn, mi'!t potenti+ll mo"ul+te prion neurotoLi$itI%7J in"i$+tin' t!e in@ol@ement o? t!ee 'ene in t!e p+t!o'enei o? prion "ie+e.

#i??erent +ppro+$!e in$lu"in' !um+n 'enome 4i"e +o$i+tion tu"ie (GA*), mouem+ppin' +n" "i??erenti+l eLpreion tu"ie !+@e u''ete" t!e +o$i+tion o? *!+"oo(*!o, !+"o4 o? prion protein)(*P) +n" % ubiDuitin li'+e (H#2) 4it! ri o?por+"i$ +n" @+ri+nt -# I%8>0J. *!+"oo i + neuron+ll eLpree" 'l$oprotein o?

unno4n ?un$tion. #ue to + $oner@e" p!iolo'i$+l +$ti@it bet4een PrP +n" *!o, itmi'!t be +$tin' on imil+r i'n+lin' p+t!4+ in !um+n prion p+t!obiolo' I>1J. /!omolo', H#2 i +n % ubiDuitin li'+e +n" i in@ol@e" in t!e ubiDuitinl+tion o? protein ?or t+r'ete" "e'r+"+tion b t!e prote+ome I>0J. !e ubiDuitinproteoometem !+ +lo been impli$+te" in prion "ie+e +n" + number o? ot!erneuro"e'ener+ti@e "ior"er I>0J.

n +not!er tu" I>2J, mi$ro+rr+ +n+li o? t!e ?ront+l $orteL o? 15 p+tient 4it!por+"i$ -# re@e+le" t!e in@ol@ement o? 79 upre'ul+te" (e.'., met+llot!ionein1 +n" 2)+n" 275 "o4nre'ul+te" 'ene (e.'., *n+ptoom+l+o$i+te" protein 25 (*AP25)mo"ul+tin' n+pti$ ?un$tion +n" pl+ti$it) $omp+re" to !e+lt! $ontrol.

Met+llot!ionein1 +n" 2 +re $teineri$! intr+$ellul+r protein 4it! + !i'! $+p+$it to bin" to <in$ +n" $opper ion +n" +re no4n to be m+inl preent in t!e $topl+m o?+tro$te o? t!e $erebr+l $orteL +n" 4!ite m+tter I>%J. Altere" eLpreion o? 'enein@ol@e" in met+l ion bin"in' +$ti@it 4oul" u''et +n +berr+nt ion !omeot+i in -#I>2J. *AP25 i in@ol@e" in mo"ul+tin' n+pti$ ?un$tion +n" pl+ti$it +n" t!en+pti$ imp+irment i + m+or p+t!olo'i$+l me$!+nim o? -# I>>J. urt!er$!+r+$teri<+tion o? t!ee 'ene i $ru$i+l to un"ert+n"in' t!e mole$ul+r b+i o? p+t!olo'i$+l pro$e o? prion "ie+e.


































Go to:

@)I"%NTI3I$ATI!N !3 $AN"I"AT% G%N%&

T+!#G+ 3#N$TI!NA' G%N!*I$ &T#"I%& IN

ANI*A' P!T%IN "I&%A&%&

t !+ been 4ell "o$umente" t!+t bei"e PP, ot!er 'ene +re +lo in@ol@e" in t!e p+t!o'enei o? prion "ie+e I>5J. 3+r'e $+le 'ene eLpreion pro?ilin' o? in?e$te" @.$ontrol +nim+l to i"enti? "i??erenti+ll eLpree" (#) 'ene m+ !elp in un"ert+n"in'no@el 'ene +n" p+t!4+ t!+t +re 4it$!e" on +n" o?? +t @+riou time point "urin' t!e p+t!o'enei o? prion "ie+e. #i??erent ?un$tion+l 'enomi$ te$!nolo'ie !+@e beenue" to "ete$te" "i??erenti+l 'ene eLpreion in$lu"in' $#A libr+rie I>6J, mA"i??erenti+l "ipl+ I>7J, uppreion ubtr+$ti@e !bri"i<+tion I>8J, mi$ro+rr+ I>95>J+n" more re$entl neLt 'ener+tion eDuen$in' I55J. !ee tu"ie in eLperiment+l +nim+lmo"el or ?rom $lini$+llin?e$te" +nim+l !+@e re@e+le" multiple 'ene +n" i'n+lin'

p+t!4+ t!+t m+ be in@ol@e" in * p+t!o'enei.

@)1) Prion elated Gene %8pression $hanges in Animal *odels

#ue to t!e +@+il+bilit o? limite" m+teri+l ?rom prionin?e$te" +mple +t pre$lini$+l +n"$lini$+l t+'e ?or !um+n +n" ot!er +nim+l; +n" "ue to t!e imil+ritie bet4een t!emoue +n" !um+n 'enome, t!e moue mo"el !+@e been ue" in e@er+l prion p+t!o'enei tu"ie. !ee mo"el !+@e pro@i"e" t!e number +n" repli$+tion reDuire"?or "ei'nin' l+r'e $+le tu"ie to i"enti? t!e 'ene o? interet +t "i??erent time pointt!rou'!out "ie+e p+t!o'enei I56J. urt!ermore, moue mo"el $+n +lo be ue" ?ortetin' t!e $+n"i"+te 'ene ?rom o@ereLprein' tr+n'eni$ to no$out, to "etermine

t!eir e??e$t on prion p+t!olo'.

n br+in tiue ?rom eLperiment+l $r+piein?e$tion +nim+l mo"el (+ble 6 6 pro@i"e +lit o? !i'! t!rou'!put tu"ie $on"u$te" in moue mo"el), "i??erenti+ll eLpree" (#)'ene !+@e been i"enti?ie" +t "i??erent t+'e o? prion "ie+e uin' mi$ro+rr+ +n+liI>7, 5760J. !e 'lob+l +n+li o? t!e o@er+ll tr+n$ription+l repone in pre$lini$+l +n"$lini$+l $entr+l ner@ou tem tiue o? mi$e in repone to prion in?e$tion re@e+le" t!+tm+n o? t!e in"i@i"u+l 'ene i"enti?ie" !+" +n +o$i+tion 4it! t!e neuro"e'ener+ti@e pro$e in prion "ie+e + 4ell + Al<!eimerN "ie+e (A#) I57J. !e "i??erenti+leLpreion o? 'ene in@ol@e" in $ellul+r tre (oLi"+ti@e tre +n" tre), +$ti@+te" +n" mito$!on"ri+l +poptoti$ p+t!4+, prote+e in!ibitor, $+l$ium bin"in' protein,

en"oome&loome ?un$tion, immunit, n+pe ?un$tion, met+l ion bin"in', +n"+$ti@+te" $!oleterol biont!ei, !+@e been !o4n in t!e $r+piein?e$te" !ippo$+mpuI58J +n" br+in I59, 60J. urt!ermore, +ll t!ee tu"ie !+@e in"i$+te" imil+ritie bet4een'ene eLpreion p+ttern ?oun" in br+in +??e$te" b A# +n" +'in', repe$ti@el.







































(+ble ; ;). #ue to in!erent limit+tion o? mi$ro+rr+ in$lu"in' eDuen$epe$i?i$ probe!bri"i<+tion, b+$'roun" +n" $ro!bri"i<+tion o? rel+te" 'ene, "i'it+l 'eneeLpreion (#G) t+' pro?ilin' uin' neLt 'ener+tion eDuen$in' 4+ ue" to $omp+ret!e tr+n$riptomi$ pro?ile o? me"ull+ tiue ?rom $+ttle in?e$te" 4it! /* I55J. !itu" i"enti?ie" 190 # tr+n$ript ?rom "i??erent p+t!4+ in$lu"in' neuro+$ti@e

li'+n"–re$eptor inter+$tion, re'ul+tion o? t!e +$tin $toeleton, ?o$+l +"!eion, *Ainter+$tion in @ei$ul+r tr+nport, $ell re$eptor i'n+lin', $+l$ium i'n+lin', Gbet+i'n+lin', +n" MAP i'n+lin'. n+""ition, t!e +' pro?ilin' 4+ u$$e?ul ini"enti?in' +""ition+l p+t!4+ lie rb/ i'n+lin', t!e $ell re$eptor, t!e nti'n+lin', +nti'en pro$ein', $toine$toine re$eptor inter+$tion, G+p un$tion, +n"t!e PPA i'n+lin' + $omp+re" to t!e pre@iou mi$ro+rr+ tu"ie on /*in?e$te"me"ull+ tiue I5%, 55J. !e $ommon # 'ene "ete$te" in +ll t!ee tu"ie I5255, 65Jon $+ttle 4ere: *100 $+l$ium bin"in' +n" +lmo"ulin; Prol+$tinrel+te" protein; GP+e,MAP ?+mil member, Hito$omp+tibilit $ompleL, $l+ , Met+llopepti"+e +n"Moin, Glut+t!ione * tr+n?er+e A, Al"oeto re"u$t+e ?+mil +n" u$le+r re$eptorub?+mil 'roup H.

+ble %.Hi'! !rou'!put Gene Lpreion *tu"ie in Prionin?e$te" #i??erent iue ?rom t!eumin+nt 3e+"in' to t!e "enti?i$+tion o? M+or un$tion+l +n"i"+te Gene & M+rer &P+t!4+

pre'ul+tion o? t!ree $!+perone in$lu"in' en"opl+mi$ reti$ulum () $!+perone,Grp9> +n" Grp170 !+ tron'l u''ete" t!e preen$e o? tre +n" t!e +$ti@+tion o?t!e un?ol"e" protein repone (P) in /*in?e$te" $+ttle I66J. !e p+ttern o? 'eneeLpreion in 4!ite bloo" $ell ?ollo4in' or+l in?e$tion o? $+ttle 4it! /o@ine +mloi"oti$pon'i?orm en$ep!+lop+t! (/A*) !+ +lo been in@eti'+te" +n" i'ni?i$+nt $!+n'e ineLpreion o? 'ene line" to +n" /$ell "e@elopment +n" +$ti@+tion, +n" toin?l+mm+tor repone 4+ ober@e" I67J. Hi'!"enit 4!ole 'enome +o$i+tiontu" in 1>% /* $+e +n" 17% $ontrol +nim+l elu$i"+te" $!romoom+l re'ion +n" poition+l $+n"i"+te 'ene +o$i+te" 4it! "ie+e I28J. !ee poition+l $+n"i"+te 'enein$lu"e !pot!eti$+l 'ene 3E521010, imil+r to 506 bin"in' protein 2 en$o"in' + protein ?rom immunop!ilin protein ?+mil 4it! + role in protein ?ol"in', leu$ineri$!repe+t +n" immuno'lobulinlie "om+in 2, 3G2, + protein no4n to be in@ol@e" in proteinprotein inter+$tion, +n" epuli@e 'ui"+n$e mole$ule ?+mil member A, +'l$ol p!op!+ti"linoitol +n$!ore" 'l$oprotein, 4it! + role + +n +Lon 'ui"+n$e protein in t!e $entr+l ner@ou tem I28J.

e$entl, tr+n$riptomi$ +n+li in t!e $+u"+l me"ull+ oblon'+t+ o? $r+piemptom+ti$ !eep uin' + = $utom "ei'ne" >L>> mi$ro+rr+ pl+t?orm i"enti?ie"





























1>8 'ene (+ble ; ;) t!+t +re prim+ril +o$i+te" 4it! t!e immune repone, iontr+nport, $ell +"!eion, +n" tr+n$ription I68J. r+n$riptome +n+li o? $r+piein?e$te"lmp! no"e +n" pleen tiue ?rom !eep !+@e re@e+le" t!e repreion o? 'ene line"to in?l+mm+tion +n" oLi"+ti@e tre, +n" t!e upre'ul+tion o? 'ene rel+te" to +poptoiI69J. e per?orme" ?irt $ompre!eni@e mi$ro+rr+ +n+li o? !i'!t!rou'!put 'ene

eLpreion +o$i+te" 4it! # "ie+e uin' bo@ine pe$i?i$ oli'o. !e "i??erenti+leLpreion o? + et o? e 'ene ?rom "i??erent p+t!4+ ?rom multiple or'+n o? #in?e$te" el in$lu"e m+or re'ul+tor +n" i'n+lin' net4or, neuron+l i'n+lin', n+pe?un$tion in neurolo'i$+l "ie+e, $+l$ium i'n+lin', +poptoi +n" $ell "e+t!, +n" immune$ell tr+??i$in' +n" in?l+mm+tor repone I70J.

n t!i re@ie4, 4e !+@e umm+ri<e" t!e emer'in' role o? ?un$tion+l 'enomi$te$!nolo'ie in i"enti?in' 'eneti$ $!+n'e 4!i$! $oul" be ue" + potenti+ll "i+'noti$ biom+rer ?or ri "etermin+tion +n" + 'ener+l in"i$+tor o? "ie+e pro'reion. Moto? t!e eLpreion pro?ilin' tu"ie per?orme" o ?+r +re in "i??erent mo"el +?ter $lini$+lmptom +ppe+r, !o4e@er, prion "ie+e +n" ot!er neuro"e'ener+ti@e "ior"er !+@e +

lon' premptomi$ p!+e I71J. A""ition+l tu"ie 4ill be ne$e+r to in@eti'+te"i??erenti+l 'ene eLpreion t!rou'! ?ull tr+n$riptomi$ +n+li ?rom +nim+l +t bot! pre$lini$+l +n" $lini$+l time point to i"enti? ne4 'ene, protein +n" p+t!4+ in@ol@e" int!e p+t!o'enei o? * in or"er to ele$t 'ene() 4!i$! $oul" be ue" + + pre$lini$+l"i+'noti$ m+rer.

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)PI!N "I&%A&%& AN" !T+%

N%#!"%G%N%ATI,% "I&!"%&

Mi?ol"in' o? t!e prion protein +n" it pro'rei@e +$$umul+tion into +''re'+te i t!e$ommon ?e+ture o? m+n m+or neuro"e'ener+ti@e "ie+e, lie A#, P+rinonN "ie+e(P#), ?rontotempor+l "ementi+, Huntin'tonN "ie+e (H#) 4!i$! i !+re" b * or prion "ior"er lie -# I72, 7%J. n +ll t!ee neurolo'i$+l "ie+e, t!ere i $ontinue"nt!ei o? mut+nt, +''re'+tionprone protein u$! + t+u (in +up+t!ie), wnu$lein(in P#), pol'lut+mine$ont+inin' protein (in H#), +n" +mloi" (in A#) ?or m+n"e$+"e be?ore neurop+t!olo' mptom +re e@i"ent I1%J. urt!ermore, t!ee proteinor protein +''re'+te in"i$+te WprionlieX p!enomenon o? -# +n" /* +n" !+@e been!o4n to pre+" to ot!er $ell +n" br+in re'ion reultin' in t!e pro'rei@e "eterior+tionI7>, 75J. Prion "ie+e +n" A# !+re ome $ommon morp!olo'i$+l +n"

p+t!op!iolo'i$+l ?e+ture in$lu"in' t!e $opper bin"in' propertie o? t!e +mloi"o'eni$ protein, oLi"+ti@e tre +n" t!e e@i"en$e o? ?ree r+"i$+l "+m+'e, t!e ?orm+tion o?+mloi" pl+Due +n" neuro?ibrill+r p+t!olo' I1%, 76J. Hitolo'i$+l +n" bio$!emi$+ltu"ie I77, 78J !+@e re$entl u''ete" t!+t Al<!eimerX "ie+e +n" * p+t!olo'iener'iti$+ll inter+$t 4it! t!e poibilit o? + "ire$t inter+$tion bet4een t!e proteinle+"in' to $roee"in' +n" in$re+e" p+t!o'enei 4it! t!e poibilit o? mole$ul+r$ro t+l bet4een bot! "ie+e. !i inter+$tion m+ "irupt inter+$tion bet4een PrP$ +n" + $ore$eptor imp+irin' t!e neuronX i'n+ltr+n"u$tion p+t!4+ le+"in' to +mloi"



































oli'omeri<+tion outi"e t!e $ell +n" intr+$ellul+r +$$umul+tion o? t+u protein le+"in' ton+pti$ pl+ti$it, +Lon+l "+m+'e +n" neuron+l "e+t! I7779J.

n +""ition to t!e $ommon !itop+t!olo'i$+l ?e+ture, oLi"+ti@e tre i'. (1 1) i +nimport+nt ?+$tor t!+t !+ been impli$+te" in t!e p+t!o'enei o? + number o?

neuro"e'ener+ti@e "ior"er I58J. !e mi?ol"in' o? protein or t!e "e@elopment o? pl+Due i ?ollo4e" b lo o? n+pe +n" poible +bnorm+litie in mito$!on"ri+l?un$tion. n$re+e" eniti@it to oLi"+ti@e tre in neuro"e'ener+ti@e "ie+e i t!rou'!+lter+tion o? +ntioLi"+nt en<me ?un$tion, +n" in$re+e" lipi" peroLi"+tion reultin' inimp+irment o? +ntioLi"+nt repone I80J. !ere i in$re+in' e@i"en$e t!+t e$on"+rmito$!on"ri+l "?un$tion b in!ibition o? e@er+l e en<me in t!e mito$!on"ri+lener' pro"u$tion p+t!4+ or t!rou'! t!e tri''erin' o? $+p+e"epen"ent +poptoio$$ur in + number o? m+or neuro"e'ener+ti@e "ie+e I81J. n +""ition, oLi"+ti@e tre+n" +poptoi in prion "ie+e reult in en"opl+mi$ reti$ulum tre t!rou'! t!e"iruption o? $+l$ium !omeot+i in t!e $ell $+uin' $+l$ium o@erlo+" in t!e $topl+mle+"in' to n+pti$ lo +n" neuron+l "e+t! I82J. Et!er tu"ie !+@e +lo re@e+le" t!+t t!e

o@er+ll le@el o? oLi"+ti@e "+m+'e to protein, lipi" +n" #A m+ reult in ubiDuitin prote+ome "?un$tion le+"in' to neuron+l "e'ener+tion I8%J. *in$e t!e mole$ul+r p+t!4+ in@ol@e" in "i??erent neuro"e'ener+ti@e "ie+e +re imil+r, ?urt!er tu"ie toeLplore t!ee mole$ul+r inter+$tion, uin' !i'! t!rou'!put ?un$tion+l 'enomi$te$!nolo'ie $ombine" 4it! ne4 bioin?orm+ti$ $+p+bilitie, 4ill pro@i"e + ne4$on$eptu+l ?r+me4or ?or t!e p+t!o'enei o? "i??erent neuro"e'ener+ti@e "ie+e +n"4ill !+@e import+nt t!er+peuti$ impli$+tion.

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ntil no4, mot o? t!e ?un$tion+l 'enomi$ tu"ie !+@e emploe" mi$ro+rr+ +n"'enome 4i"e +o$i+tion tu"ie to i"enti? potenti+l $+n"i"+te 'ene or p+t!4+in@ol@e" in prion "ie+e in "i??erent mo"el or or'+nim. it! t!e re$ent +"@+n$e inneLt 'ener+tion eDuen$in', eLome eDuen$in', l+r'e $+le "+t+ inte'r+tion +n" "+t+minin', it !oul" be poible to in@eti'+te ot!er e re'ul+tor in$lu"in' miA, +n"tr+n$ription ?+$tor pl+in' + role in t!e p+t!o'enei me$!+nim I8>J. *ome prelimin+r tu"ie +re be'innin' to et+bli! t!e role o? miA in prion "ie+e. !e?irt $ompre!eni@e mi$ro+rr+ +n+li o? miA eLpreion in t!e br+in o? mi$ein?e$te" 4it! moue+"+pte" $r+pie reporte" t!e "ere'ul+tion o? 15 miA$ontrollin' + number o? 'ene +n" i'n+lin' p+t!4+ "urin' prion in"u$e"


























neuro"e'ener+tion I85J. Anot!er tu" pro@i"e" e@i"en$e o? upre'ul+tion o? miA1>6+ in por+"i$ reut<?el"t-+ob "ie+e (-#) +n" Gertm+nn*tr+uler*$!einern"rome (G**) u''etin' it role in inn+te immune repone +n" +nti@ir+l immunitI86J. ort!$omin' "ire$tion o? ree+r$! 4ill ?o$u on + $oor"in+te" +ppro+$! to lintr+n$riptome +n" mi$roAome "+t+ 4it! eLteni@e $omput+tion+l +n+li, neLt

'ener+tion eDuen$in' tu"ie p+nnin' t!e entire 'enome or eLome, +n+li o?tru$tur+l 'eneti$ @+ri+tion ($op number @+ri+tion t!rou'! "eletion, "upli$+tion, +n"in@erion) +n" 'enome 4i"e +o$i+tion +n+li. All t!ee tu"ie i'. (6 6) 4ill pro@i"ene4 ini'!t o? t!e re'ul+tor net4or in@ol@e" in prion p+t!o'enei o? !um+n +n"+nim+l prion "ie+e. Prion +re +lo emer'in' + WeLtreme $+e o? epi'eneti$in!erit+n$eX +n" prion b+e" me$!+nim m+ in?luen$e 'eneti$ in?orm+tion I87J.n"ert+n"in' o? t!e epi'eneti$ in?orm+tion in +""ition to t!e 'eneti$ in?orm+tion i be$omin' import+nt ?or t!e pre@enti@e "i+'noi +n" tre+tment o? "ie+e I88J. !e+@+il+bilit o? neLt 'ener+tion eDuen$in' te$!nolo'ie 4ill empo4er t!e tu" o?epi'eneti$ @+ri+tion in$lu"in' #A met!l+tion, !itone mo"i?i$+tion, +n" $!rom+tin+$$eibilit 4!i$! m+ be in@ol@e" in prion +o$i+te" neuro"e'ener+ti@e "ior"er.

urt!ermore, tu"ie uin' ?un$tion+l proteomi$ +n" ne4 p!iolo' te$!niDue u$! +l+er $+pture mi$ro"ie$tion on ubpopul+tion o? $ell in pre +n" potmptomi$ p!+e o? prion +n" ot!er neuro"e'ener+ti@e "ie+e 4ill $omplement t!e 'enomi$tu"ie to "etermine ele$ti@e biom+rer.

i'. (2)n"ert+n"in' o? $ompleL prion "ie+e: "enti?i$+tion o? 'ene +n" 'eneti$ m+rer

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2. A'u<:765–775. IPubMe"J%. mr+n M, M+!moo" *. An o@er@ie4 o? +nim+l prion "ie+e. =irolo' -. 2011;8:>9%– 501. IPM ?ree +rti$leJ IPubMe"J>. Hu<+re4i$! 3, *iemen AG, /oot! *A. Appli$+tion o? Womi$X to prion biom+rer

"i$o@er. -. /iome"i$ine /iote$!. 2010. "oi:10.1155&2010&61%50>. IPM ?ree +rti$leJIPubMe"J5. A'u<2%:127–129. IPubMe"J6. ilemit! -, +n -/, Atinon M-. /o@ine pon'i?orm en$ep!+lop+t!:epi"emiolo'i$+l tu"ie on t!e ori'in. =et. e. 1991;128:99–20%. IPubMe"J7. +t!+non , ilemit! -, Griot . /o@ine pon'i?orm en$ep!+lop+t! (/*): $+ue+n" $oneDuen$e o? + $ommon our$e epi"emi$. Am. -. pi"emiol. 1997;1>5:959–969.IPubMe"J8. Pruiner */. Mole$ul+r biolo' o? prion "ie+e. *$ien$e. 1991;252:1515–1522.IPubMe"J

9. P+n M, /+l"4in M, 'uen -, G+et M, *erb+n A, Grot! #, Me!l!orn , Hu+n' ,letteri$ -, o!en . on@erion o? w!eli$e into !eet ?e+ture in t!e ?orm+tiono? t!e $r+pie prion protein. Pro$. +tl. A$+". *$i. 199%;90:10962–10966. IPM ?ree+rti$leJ IPubMe"J10. /il+n , l$ G, Gi+$!in G, +p+"ori A, !uo@ , Pl+@e$ -, 3e'n+me G. o4+r" t!eMole$ul+r /+i o? n!erite" Prion #ie+e: M *tru$ture o? t!e Hum+n Prion Protein4it! =210 Mut+tion. -. Mol. /iol. 2011;>12:660–67%. IPubMe"J11. Pruiner */. Prion. Pro$. +tl. A$+". *$i. *A. 1998;95:1%%6%–1%%8%. IPM ?ree+rti$leJ IPubMe"J12. A'u<;116:%1%–%27. IPubMe"J1%. r+er H, #i$inon AG. *tu"ie o? t!e lmp!oreti$ul+r tem in t!e p+t!o'enei o? $r+pie: t!e role o? pleen +n" t!mu. -. omp. P+t!ol. 1978;88:56%–57%. IPubMe"J1>. imberlin H, +ler A. P+t!o'enei o? moue $r+pie: "n+mi$ o? +'entrepli$+tion in pleen, pin+l $or" +n" br+in +?ter in?e$tion b "i??erent route. -. omp.P+t!ol. 1979;89:551–562. IPubMe"J15. M+bbott A, M+$P!eron GG. Prion +n" t!eir let!+l ourne to t!e br+in. +turee@. Mi$robiol. 2006;>:201–211. IPubMe"J16. /+ler , Ee$! /, *$ott M, et+4+ #, +l$!li M, Grot! , M$inle MP,Pruiner */, eim+nn . *$r+pie +n" $ellul+r PrP io?orm +re en$o"e" b t!e +me$!romoom+l 'ene. ell. 1986;>6:>17–>28. IPubMe"J17. et+4+ #, Goo"m+n PA, Miren"+ AA, M$inle MP, +rlon GA, Pruiner */.#itin$t prion protein in !ort +n" lon' $r+pie in$ubt+tion perio" mi$e. ell.1987;51:651–662. IPubMe"J18. Hi+o , /+er H, ro4 -, Poulter M, E4en , er4illi'er -#, et+4+ #, Ett -,Pruiner */. 3in+'e o? + prion protein miene @+ri+nt to Gertm+nn*trùlern"rome. +ture. 1989;%%8:%>2–%>5. IPubMe"J19. G+briel -M, Ee$! /, ret<$!m+r H, *$ott M, Pruiner */. Mole$ul+r $lonin' o? +$+n"i"+te $!i$en prion protein. Pro$. +tl. A$+". *$i. 1992;89:9097–9101. IPM ?ree+rti$leJ IPubMe"J























































20. A'u<6:795–805. IPubMe"J22. on'+n , î+n'lon' 3, 3+n!ui 3, î+n'un 3, uun . @olution +n"

"i??erenti+tion o? t!e prion protein 'ene (PP) +mon' pe$ie. -. Here"it.2008;99:6>7–652. IPubMe"J2%. olb #, Pruiner */. Prion. ol" *prin' H+rb. Perpe$t. /iol. 2011;%:+0068%%.IPM ?ree +rti$leJ IPubMe"J2>. Hernan"e<*an$!e< -, +""in'ton #, iener P, H+le *, illi+m -3. Genome4i"e e+r$! ?or m+rer +o$i+te" 4it! bo@ine pon'i?orm en$ep!+lop+t!. M+mm.Genome. 2002;1%:16>–168. IPubMe"J25. !+n' , "e onin' #-, Hernan"e<*an$!e< -, H+le *, illi+m -3, iener P.M+ppin' o? multiple Du+ntit+ti@e tr+it lo$i +??e$tin' bo@ine pon'i?orm en$ep!+lop+t!.Geneti$. 200>;167:186%–1872. IPM ?ree +rti$leJ IPubMe"J26. Mur"o$! /M, l+4on M3, 3+e'rei" , *tot!+r" P, *ettle M, M$+ *, Pr++"

A, +n' , Moore **, illi+m -3. A 2$M 'enome4i"e $+n o? urope+n Holtein$+ttle +??e$te" b $l+i$+l /*. /M Genet. 2010;29:11–20. IPM ?ree +rti$leJIPubMe"J27. Mur"o$! /M, l+4on M3, Yue *, /+u , M$+ *, *ettle M, +po?erri ,3+e'rei" , illi+m -3, Moore **. PP !+plotpe +o$i+te" 4it! $l+i$+l /*in$i"en$e in urope+n Holtein $+ttle. P3o* E. 2010;5:pii: e12786. IPM ?ree +rti$leJIPubMe"J28. Mur"o$! /M, Mur"o$! G, *ettle M, M$+ *, illi+m -3, Moore **. Genome4i"e $+n i"enti?ie lo$i +o$i+te" 4it! $l+i$+l /* o$$urren$e. P3o* E. 2011;6e26819."oi: 10.1%71&ourn+l.pone. 0026819. IPM ?ree +rti$leJ IPubMe"J29. Al@+re< 3, Arr+n< --, *+n Primiti@o . "enti?i$+tion o? + ne4 leu$ine !+plotpe(A3O) +t $o"on 15> in t!e o@ine prion protein 'ene in *p+ni! !eep. - Anim. *$i.2006;2:259–265. IPubMe"J%0. Moreno , oe""u GM, *$!ibler 3, oi' A, Mo+<+miGou"+r<i , An"reolettiE, $!enne , 3+ou #, *$!el$!er , ribiu P, 3+urent P, =+im+n #, len -M."enti?i$+tion o? ne4 Du+ntit+ti@e tr+it lo$i (ot!er t!+n t!e PP, 'ene) mo"ul+tin' t!e$r+pie in$ub+tion perio" in !eep. Geneti$. 2008;179:72%–726. IPM ?ree +rti$leJIPubMe"J%1. Moreno , 3+ntier , 3+ntier , *+rr+"in P, len -M. #ete$tion o? ne4 Du+ntit+ti@etr+it lo$i ?or u$eptibilit to tr+nmiible pon'i?orm en$ep!+lop+t!ie in mi$e.Geneti$. 200%;165:2085–2091. IPM ?ree +rti$leJ IPubMe"J%2. 3lo" *, p!ill -/, +r'oni P=, i!er M, ollin'e -. "enti?i$+tion o? 'eneti$lo$i +??e$tin' moue+"+pte" bo@ine pon'i?orm en$ep!+lop+t! in$ub+tion time in mi$e. euro'eneti$. 2002;>:77–81. IPubMe"J%%. Me+" *, Poulter M, p!ill -, /e$ -, !it?iel" -, ebb , +mpbell , A"+mon G,#eri<ioti P, +bri. G+mbetti P, on' O, ou , P+r$!i P, !en *G. *por+"i$ +n" ?+mili+l -#:$l+i?i$+tion +n" $!+r+$teri+tion. /r. Me". /ull. 200%;66:21%–2%9. IPubMe"J



















































>9. iemer , ei"!ol" *, /ur4inel M, *$!4+r< A, *$!ult< -, r+t<$!m+r -, Monnin', /+ier M. Gene eLpreion pro?ilin' o? $r+piein?e$te" br+in tiue. /io$!em./iop!. e. ommun. 200>;%2%:556–56>. IPubMe"J50. Green4oo" A#, Hor$! M, *ten'el A, =orber' , 3ut<n G, M++ , *$!`"ler *,r?le =, /e$er -, *$!`t<l H, 3eibMf$! . ell line "epen"ent A eLpreion

pro?ile o? prionin?e$te" moue neuron+l $ell. -. Mol. /iol. 2005;%>9:>87–500.IPubMe"J51. *orenen G, Me"in+ *, P+r$!+liu #, P!illipon , oberton , /oot! *A.ompre!eni@e tr+n$ription+l pro?ilin' o? prion in?e$tion in moue mo"el re@e+lnet4or o? reponi@e 'ene. /M Genom. 2008;9:11>–127. IPM ?ree +rti$leJIPubMe"J52. !+ni+ /, Almei"+ 3, /+u , +ni'u$!i M, illi+m -3, /+rre"+ #, Moore **,Gu+n 33. Mi$ro+rr+ +n+li o? "i??erenti+ll eLpree" 'ene ?rom PeerX p+t$!e o?$+ttle or+ll $!+llen'e" 4it! bo@ine pon'i?orm en$ep!+lop+t!. -. oLi$ol. [email protected]+lt! A. 2009;72:1008–101%. IPubMe"J5%. Almei"+ 3M, /+u , !+ni+ /, +ni'u$!i M, illi+m -3, Moore **, Gu+n 33.

Gene eLpreion in t!e me"ull+ ?ollo4in' or+l in?e$tion o? $+ttle 4it! bo@ine pon'i?ormen$ep!+lop+t!. -. oLi$ol. n@iron. He+lt! A. 2011;7>:110–126. IPubMe"J5>. Almei"+ 3M, /+u , illi+m -3, Moore **, Gu+n 33. Mi$ro+rr+ +n+li in$+u"+l me"ull+ o? $+ttle or+ll $!+llen'e" 4it! bo@ine pon'i?orm en$ep!+lop+t!.Genet. Mol. e. 2011;10 #E: !ttp:&&"L."oi.or'&10.>2%8 . IPubMe"J55. /+u , Almei"+ 3, Elon , Men' Y, illi+m -3, Moore **, Gu+n 33.r+n$riptome +n+li o? t!e me"ull+ tiue ?rom $+ttle in repone to bo@inepon'i?orm en$ep!+lop+t! uin' "i'it+l 'ene eLpreion t+' pro?ilin'. -. oLi$ol.n@iron. He+lt! A. 2011;7>:127–1%7. IPubMe"J56. 3lo" *, Me+" *, ollin'e -. Geneti$ o? prion "ie+e. opi$ urr. !em.2011;%05:1–22. IPubMe"J57. /oot! *, /o4m+n , /+um'+rtner , *orenen G, oberton , oult!+rt M,P!illipon , *omor+i 3. "enti?i$+tion o? $entr+l ner@ou tem 'ene in@ol@e" in t!e!ot repone to t!e $r+pie +'ent "urin' pre$lini$+l +n" $lini$+l in?e$tion. -. Gen. =irol.200>;85:%>59–%>71. IPubMe"J58. /ro4n A, ebu *, M$immie *, oberton , illi+m A, +<+erle -. GeneLpreion pro?ilin' o? t!e pre$lini$+l $r+piein?e$te" !ippo$+mpu. /io$!em. /iop!.e. ommun. 2005;%%>:86–95. IPubMe"J59. î+n' , in"l E, un$! G, #u'+ M, o!lm+nn A, #iere , etner M,ret<$!m+r HA. "enti?i$+tion o? "i??erenti+ll eLpree" 'ene in $r+piein?e$te"moue br+in b uin' 'lob+l 'ene eLpreion te$!nolo'. -. =irol. 200>;78:11051– 11060. IPM ?ree +rti$leJ IPubMe"J60. *inner P-, Abb+i H, !eebro /, +$e , eill , H+e A. Gene eLpreion+lter+tion in br+in o? mi$e in?e$te" 4it! t!ree tr+in o? $r+pie. /M Genomi$.2006;7:11>–127. IPM ?ree +rti$leJ IPubMe"J61. im HE, *n"er GP, /l+<e M, +$e , !eebro /, *inner P-. Prion "ie+ein"u$e" +lter+tion in 'ene eLpreion in pleen +n" br+in prior to $lini$+l mptom.A"@ Appl. /ioin?orm. !em. 2008;1:29–50. IPM ?ree +rti$leJ IPubMe"J62. H4+n' #, 3ee Y, Yoo H, Ge!lenbor' , !o -, Petriti /, /+Lter #, Pitti$ ,Youn' , *pi$er #, Pri$e #, Ho!m+nn -G, #eArmon" *-, +rlon GA, Hoo" 3. A







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tem +ppro+$! to prion "ie+e. Mol. *tem /iol. 2009;5:252–255. IPM ?ree+rti$leJ IPubMe"J6%. Hu<+re4i$! 3, Me"in+ *, oberton , P+r$!+liu #, /oot! *A. r+n$ription+lmo"ul+tion in + leuo$te"eplete" pleni$ $ell popul+tion "urin' prion "ie+e. -.oLi$ol. n@iron. He+lt! A. 2011;7>:150>–1520. IPubMe"J

6>. orto+ , +tell ^, =i"+l , ot+ , ui< "e =ill+ M"el , *an$!e< A, /+r$el A,orre -M, Pum+rol+ M, Arixo -. entr+l ner@ou tem 'ene eLpreion $!+n'e in +tr+n'eni$ moue mo"el ?or bo@ine pon'i?orm en$ep!+lop+t!. =et. e. 2011;>2:109– 12%. IPM ?ree +rti$leJ IPubMe"J65. +n' Y, î+n' , H+4in *A, ret<$!m+r HA, in"t E. r+n$ription+l $!+n'ein t!e br+in o? $+ttle or+ll in?e$te" 4it! t!e bo@ine pon'i?orm en$ep!+lop+t! +'ent pre$e"e "ete$tion o? in?e$ti@it. -. =irol. 2009;8%:9>6>–9>7%. IPM ?ree +rti$leJIPubMe"J66. +n' Y, î+n' , err 3, ret<$!m+r HA, in"l E. r+n$ription+l +n+liimpli$+te en"opl+mi$ reti$ulum tre in /o@ine *pon'i?orm n$ep!+lop+t!. P3o*E. 2010;5 e1>207. "oi:10.1%71&ourn+l.pone.001>207. IPM ?ree +rti$leJ IPubMe"J

67. P+nelli *, *tro<<i , +po?erri , /+rbieri , +rtinelli , +pu$$i 3, 3omb+r"i G,illi+m -3. An+li o? 'ene eLpreion in 4!ite bloo" $ell o? $+ttle or+ll $!+llen'e"4it! /o@ine +mloi"oti$ pon'i?orm en$ep!+lop+t!. -. oLi$ol. n@iron. He+lt!, P+rt A.2011;7>:96–102. IPubMe"J68. il+li H, M+rtin/urriel , H+r"er , =+ron+ 3, 3+!+i -, +r+'o<+ P, Pum+rol+ M,/+"iol+ --, /oer A, /ole+ . Gene eLpreion pro?ilin' +n" +o$i+tion 4it! prionrel+te" leion in t!e me"ull+ oblon'+t+ o? mptom+ti$ n+tur+l $r+pie +nim+l. P3o*E. 2011;6 e19909. "oi: 10.1%71&ourn+l.pone.0019909. IPM ?ree +rti$leJ IPubMe"J69. Goner A, oup++ *, oter -, Hunter , Hopin -. r+n$ription+l pro?ilin' o? perip!er+l lmp!oi" tiue re@e+l 'ene +n" net4or line" to **/P&1 $r+pie p+t!olo' in !eep. =et. Mi$robiol. 2011;15%:218–228. IPubMe"J70. /+u , Almei"+ 3M, #u"+ *, Gr+!+m , <ub *, Moore **, Gu+n 33. GeneeLpreion +lter+tion in ro$ mount+in el in?e$te" 4it! $!roni$ 4+tin' "ie+e. Prion.2012. IPM ?ree +rti$leJ IPubMe"J71. /enetti , Gutin$i$! *, 3e'n+me G. Gene eLpreion pro?ilin' +n" t!er+peuti$inter@ention in neuro"e'ener+ti@e "ie+e: + $ompre!eni@e tu" on potenti+lit +n"limit. Lpert Epin. #ru' #i$o@. 2012;7:2>5–258. IPubMe"J72. !iti , #obon M. Protein mi?ol"in', ?un$tion+l +mloi" +n" !um+n "ie+e.Annu. e@. /io$!em. 2006;75:%%%–%66. IPubMe"J7%. -ellin'er A. nter+$tion bet4een p+t!o'eni$ protein in neuro"e'ener+ti@e "ior"er.-. ell Mol. Me". 2011. #E: 10.1111&.1582>9%>.2011.01507.L. IPubMe"J7>. rot /, #i+mon" M. Prionlie me$!+nim in neuro"e'ener+ti@e "ie+e. +turee@. euro$i. 2010;11:155–159. IPM ?ree +rti$leJ IPubMe"J75. Guet , *il@erm+n M, Pori!e@ , EXeil MA, Gr+" 3, +!m+n .Gener+liL+tion o? t!e prion !pot!ei to ot!er neuro"e'ener+ti@e "ie+e: An imper?e$t?it. -. oLi$ol. n@iron. He+lt!, P+rt A. 2011;7>:1>%%–1>59. IPubMe"J76. +tell+ni -, Perr G, *mit! MA. Prion "ie+e +n" Al<!eimerX "ie+e, p+t!o'eni$ o@erl+p. A$t+. eurobiol. Lp. 200>;6>:11–17. IPubMe"J77. ie M, Mu$e 3. A prion protein $onne$tion. +ture. 2009;257:1090–1091.IPubMe"J



















































78. Mor+le , tr+"+ 3#, #i+<pinoL+ , Mor+le*$!ei!in' #, -+r+ M, +till+ -,*oto . Mole$ul+r $ro t+l bet4een mi?ol"e" protein in +nim+l mo"el o? Al<!eimerX+n" prion "ie+e. -. euro$i. 2010;%0:>528–>5%5. IPM ?ree +rti$leJ IPubMe"J79. *oto . r+nmiible protein: Lp+n"in' t!e prion !ere. ell. 2012;1>9:968–977.IPM ?ree +rti$leJ IPubMe"J

80. Mil!+@et E, 3e!+mnn *. ELi"+ti@e tre +n" t!e prion protein in tr+nmiiblepon'i?orm en$ep!+lop+t!i. /r+in ee+r$! e@ie4. 2002;%8:%28–%%9. IPubMe"J81. M+n$uo M, *i$ili+no G, iloto M, Murri 3. Mito$!on"ri+l "?un$tion +n"Al<!eimerX "ie+e: ne4 "e@elopment. -. Al<. #i. 2006;9:111–117. IPubMe"J82. *oto , *+t+ni . !e intri$+te me$!+nim o? neuro"e'enr+tion in prion "ie+e.ren" Mol Me"i$ine. 2011;17:1>–2>. IPM ?ree +rti$leJ IPubMe"J8%. Gi+on /, 3ee =MY, ro+no4i -O. !e rel+tion!ip bet4een oLi"+ti@e&nitr+ti@etre +n" p+t!olo'i$+l in$luion in Al<!eimerN +n" P+rinonN "ie+e. ree +"i$+l/iol. Me"i$ine. 2002;%2:126>–1275. IPubMe"J8>. Pro@ot P. Mi$roA + + mole$ul+r b+i ?or ment+l ret+r"+tion, Al<!eimerN +n" prion "ie+e. /r+in e. 2010;1%%8:58–66. IPM ?ree +rti$leJ IPubMe"J

85. *+b+ , Goo"m+n #, Hu<+re4i$! 3, oberton , /oot! *A. A miA i'n+tureo? prion in"u$e" neuro"e'ener+tion. P3o* Ene. 2008;%:e%652. IPM ?ree +rti$leJIPubMe"J86. 3ui4 -, #u+ P, Po'ue A, i$en , Hill -M. pre'ul+tion o? mi$ro A1>6+(miA1>6+), + m+rer ?or in?l+mm+tor neuro"e'ener+tion, in por+"i$ reut<?el"t-+ob "ie+e (-#) +n" Gertm+nn*tr+uler*$!einer (G**) n"rome. -. oLi$ol.n@iron. He+lt! A. 2011;7>:1>60–1>68. IPM ?ree +rti$leJ IPubMe"J87. H+l?m+nn , 3in"Duit *. pi'eneti$ in t!e eLtreme: prion +n" t!e in!erit+n$e o?en@ironment+ll +$Duire" tr+it. *$ien$e. 2010;%%0:629–6%2. IPubMe"J88. !+!4+n , ont++l *, o+ *. !e multi"imenion+l n+ture o? epi'eneti$in?orm+tion +n" it role in "ie+e. #i$o@. Me". 2011;11:2%%–2>%. IPubMe"J

Jurnal F

Virulence. 2013 July 1; 4(5): 373–383.Publise! "nline 2013 #$ril 30. !"i: 10.4161%&iru.24838PMCID: P'3714129

Infectious particles: stress: and induced

prion amyloids

# uniyin* $ers$ec+i&e,-ur- '-nueli!is#u+"r in"r-+i"n / #r+icle n"+es / "$yri*+ -n! ,icense in"r-+i"n /" +":


















http://dx.doi.org/10.4161%2Fviru.24838

http://www.ncbi.nlm.nih.gov/pubmed/?term=Manuelidis%20L%5Bauth%5D






















http://dx.doi.org/10.4161%2Fviru.24838

http://www.ncbi.nlm.nih.gov/pubmed/?term=Manuelidis%20L%5Bauth%5D







Abstract

r-nsissible ence$-l"$-+ies (s) -re belie&e! by -ny +" -rise bys$"n+-ne"us c"n&ersi"n " "s+ $ri"n $r"+ein (PrP) in+" -n inec+i"us -yl"i!(PrPres PrPc) i+"u+ nucleic -ci!. '-ny -*en+s resi!e in +e

en&ir"nen+ i+ inec+i"n c"n+r"lle! by $ublic e-l+ e-sures. eseinclu!e +e !is-$$e-r-nce " uru i+ +e cess-+i"n " ri+u-l c-nnib-lis+e !r--+ic re!uc+i"n " e$i!eic b"&ine ence$-l"$-+y () by re"&-l" c"n+-in-+e! ee! -n! +e l-c " en!eic scr-$ie in *e"*r-$ic-llyis"l-+e! #us+r-li-n see$ i+ susce$+ible PrP *en"+y$es. ile $ri"n $r"+ein"!elin* -s en*en!ere! -n in+ense "cus "n c""n +y$es " $r"+einis"l!in* -n! -yl"i! "r-+i"n in !i&erse "r*-niss -n! !ise-ses +ebi"l"*ic-l c-r-c+eris+ics " inec+i"us -*en+s -n! +eir rec"*ni+i"n by+e "s+ -s "rei*n en+i+ies r-ises se&er-l un!-en+-l ne !irec+i"ns "rrui+ul in&es+i*-+i"n suc -s: (1) unrec"*nie! icr"bi-l -*en+s in +een&ir"nen+-l e+-*en"e +-+ -y c-use l-+en+ neur"!e*ener-+i&e!ise-se (2) +e e&"lu+i"n-ry s"ci-l -n! $r"+ec+i&e unc+i"ns " !ieren+

-yl"i! $r"+eins in !i&erse "r*-niss r" b-c+eri- +" --ls -n! (3)-yl"i! "r-+i"n -s - bene<ci-l inn-+e iune res$"nse +" s+ress(inec+i"us -n! n"ninec+i"us). is inn-+e $r"cess "e&er "nce ini+i-+e!c-n bec"e uns+"$$-ble in -cceler-+e! neur"n-l -*in*.Keywords: +r-nsissible ence$-l"$-+ies en&ir"nen+-l $-+"*ensl-+ency ye-s+ $ri"ns bi"<ls e+-*en"e -*in* #leier !ise-seP-rins"n !ise-se nucleic -ci!s= = +"l! i. "ul! e lie i+ "ul! >-$"le"n?er+ru!e +ein" +":

Introduction

e $ur$"se " +is $ers$ec+i&e is +" c"unic-+e se&er-l un!-en+-lbi"l"*ic e-+ures " inec+i"ns +-+ -y n"+ be -$$-ren+ +" scien+is+s "!" n"+ is"l-+e -n! c-r-c+erie inec+i"us $-r+icles "r -n-lye !ieren+ -*en+s+r-ins. #+ i* ul+i$lici+y -*en+s c-n in!uce $-+"l"*ic-lis"l!in* " "s+ PrP in+" PrPres -yl"i!. @"e&er inec+i"n is n"+ reAuire!"r +is c"n&ersi"n -n! *ene+ic "s+ PrP c"!in* u+-+i"ns -re suBcien+ +"c-use PrP -yl"i! $l-Aues i+ n" inec+i&i+y.14 CPri"nD -yl"i! s+-+es inye-s+ -n! b-c+eri- +-+ l-c +e inec+i"us c-r-c+eris+ics " --li-n sillus+r-+e -yl"i! c""n-li+ies -s ell -s +e unc+i"n-l !i&ersi+y " $r"+ein-**re*-+i"n in e&"lu+i"n. Eni+y in +e C$ri"nD <el! rel-+es -yl"i! $r"cessesbu+ n"+ +e !i&erse inci+in* c-uses " $r"+ein -**re*-+i"n. #u+"c-+-ly+ic PrP

res -ccuul-+i"n "ll"s - -re!ly !ieren+ +r-Fec+"ry +-n +e re$lic-+i"n" inec+i"us $-r+icles -s !e+-ile! bel". ec-use PrP b-n! $-++ernsnei+er c"rrel-+e i+ n"r $re!ic+ -*en+ s+r-in $r"$er+ies +-+ -re $reser&e!-cr"ss s$ecies n"nPrP "lecules us+ !e+erine s+r-in c-r-c+eris+ics.'--ls in+er-c+ i+ +rilli"ns " icr""r*-niss "n +e sin -n! in +e-lien+-ry +r-c+ $"sin* -ny "$$"r+uni+ies "r eGc-n*e -n!%"rinc"r$"r-+i"n " "rei*n nucleic -ci!. inec+i"us -*en+s c-n re$resen+ +e+i$ " +e iceber* " i!!en en&ir"nen+-l $-+"*ens +-+ c-use l-+e "nse+!ise-se.










H"r si$lici+y c"$"si+e !-+- -re <rs+ br"-!ly su-rie! i+illus+r-+i"ns " elles+-blise! -c+s. s by !e<ni+i"n -re - *r"u$ "rel-+e! --li-n inec+i"ns +-+ -re le+-l "nce +ey in&-!e +e br-in.#c+i&e br-in inec+i"n se$-r-+es s r" "+er neur"!e*ener-+i&e !ise-sessuc -s #leier !ise-se (#I) -n! $"s+ence$-li+ic ($"s+inec+i"us)P-rins"n !ise-se +-+ s-re $r"+ein is"l!in* ec-niss -n! -yl"i!

$en"+y$es bu+ -re n"+ inec+i"us. #yl"i! $l-Aues -&e l"n* been n"n +""r in +e br-ins " n"r-l "l!er -ni-ls $-r+icul-rly $ri-+es -n!in"cul-+i"n " #I -yl"i! ""*en-+es in +e br-in "nly -cceler-+es -*in*bu+ !"es n"+ +r-nsi+ - re$lic-+in* inec+i"us -*en+. 5 e r-re *ene+ic c-ses" u-n #I -n! $ri"n $-+"l"*y -l"n* i+ +r-ns*ene (*) "!els "r #I-yl"i! -n! PrP -yl"i! !e$"si+i"n un!ersc"re n"ninec+i"us c-uses "+e s-e en!s+-*e $en"+y$e "r -yl"i! sc-r. uul-+i&e en&ir"nen+-l-c+"rs inclu!in* +"Gins -n! $-s+ inec+i"ns +-+ c-n lii+ +e lies$-n " n"n!i&i!in* neur"ns -re liely +" c-use +e "re c""n "rs n"ninec+i"us#I.6 =n c"n+r-s+ - "rei*n inec+i"us -*en+ is +e r""+ c-use " s - -c++-+ -s been "bscure! by +e -ssu$+i"n +-+ "s+enc"!e! PrPres is +einec+i"us -*en+. Kr -s "re $r"ibi+i&ely s+-+e!: CPri"ns -re c"$"se!

s"lely " +e !ise-sec-usin* $ri"n $r"+ein (PrPc)D.7 is eGclusi&e &iec"n+inues +" be $r"ul*-+e!89 e&en +"u* "+er "lecules inclu!in*nucleic -ci!s c-n be reAuire! "r re$lic-+i"n " inec+i"us -*en+s.10

e s+ruc+ure -n! in+e*r-l "lecules " +e inec+i"us $-r+icle re-inun!e<ne!. " !-+e PrPres i+sel -s -ile! +" ul<lle! L"c $"s+ul-+es.1112 L"c $"s+ul-+es re-in $-r+icul-rly rele&-n+ n" bec-use rec"bin-n+ -n!syn+e+ic nucleic -ci!s i+"u+ +e nee! "r cul+ure -re suBcien+ +" recre-+einec+i"n -n! i+s c-r-c+eris+ic !ise-se $en"+y$e -s s"n "r $"li"&irus.iil-rly -ny recen+ in&es+i*-+i"ns -&e -++e$+e! +" $r"&e +e $ri"ny$"+esis by "cusin* "n +es+ +ube -u+"c-+-ly+ic c"n&ersi"ns " n"r-l PrP+" - is"l!e! $resu-bly inec+i"us PrPres. =n +ese eG$erien+sinec+i"us -+eri-l is <rs+ use! +" s+-r+ "r Csee!D +e -yl"i!"*enic $r"cess.

ese -yl"i! c"n&ersi"n re-c+i"ns seAuen+i-lly re$lenise! i+ uninec+e!-+eri-l suc -s n"r-l br-in ""*en-+es +y$ic-lly *ener-+e en"r"us-"un+s " PrPres i+ li++le "r n" inec+i&i+y. us +e is"l!e! PrPres$r"+ein -l"ne is n"+ necess-rily inec+i"us. PrPres -s -ls" been *ener-+e!r" n"r-l br-in. is s"s +-+ PrPres "r-+i"n -n! inec+i"us -*en+re$lic-+i"n -re +" !ieren+ $r"cesses.'-ny s+u!ies -cn"le!*e +-+ s"e "+er Cc"-c+"rD is reAuire! +" -ePrP inec+i"us101314 bu+ "nly "ne *r"u$ -s re$"r+e! +-+ rec"bin-n+ PrP(recPrP) c-n be c"n&er+e! in+" -n inec+i"us "r i+"u+ -ny -ni-l !eri&e!-!!i+i&es "r Csee!sD.15 is resul+ -s ne&er been re$lic-+e! by "+ers "&er+e $-s+ 8 y -n! seri-l +r-nsissi"ns r" +-+ recPrP in + ice re&e-le!incub-+i"n +ies -n! neur"$-+"l"*y " +eir l-b"r-+"ry scr-$ie s+r-in (M',);l-b"r-+"ry c"n+-in-+i"n is -n -cn"le!*e! $r"ble in +es+ +ube PrPresc"n&ersi"ns.16 #n"+er *r"u$ -s -ls" cl-ie! in +eir -bs+r-c+ +-+ inec+i&i+yCc-n be *ener-+e! s"lely r"N recPrP i+"u+ -ny --li-n "r syn+e+icc"-c+"rsD bu+ +e eG$erien+-l !e+-ils s" +-+ - s+-n!-r! scr-$ie br-inPrPres $re$-r-+i"n n"n +" c"n+-in inec+i&i+y (-s ell -s nucleic -ci!) -s-!!e! +" see! +is recPrP re-c+i"n.17 =n - s+u!y +-+ -y be "re c"n&incin*+issue !eri&e! li$i!s ere -!!e! +" recPrP +" $r"!uce unusu-lly i* le&els "l-blie scr-$ie inec+i&i+y.18 Iurin* +e $-s+ 3 y +is resul+ -$$-ren+ly -s n"+





































been re$r"!uce! elseere by in!e$en!en+ in&es+i*-+"rs. ubseAuen+c"n&ersi"n s+u!ies i+ li$i! -n! syn+e+ic $"ly(r#) M># -ls" s"e! "nly&ery -r*in-l inec+i&i+y in -ni-ls -n! Aues+i"n-ble PrPres $-+"l"*y inc"n+r-s+ +" -!!e! +issue !eri&e! M>#.19 us -n -*en+ M># c-nn"+ be rule!"u+ -s cl-ie!. >"+i+s+-n!in* +e !i-*n"s+ic $"+en+i-l " +ese PrPc"n&ersi"ns20 +e $ur$"se " +is re&ie is +" c"&er subs+-n+i-l bi"l"*ic-l -n!

-n-ly+ic-l e&i!ence +-+ in&i+es - "re inclusi&e -$$reci-+i"n " -l+ern-+i&e-*en+ c"nce$+s. =n $-r+icul-r +e en&ir"nen+-l s"urce " inec+i"n +e&-rie+y -n! $ersis+ence " !ieren+ -*en+ s+r-ins +e s$ecies -n! cellres$"nses +" +ese !is+inc+ -*en+ s+r-ins -n! +e $resence " nucleic -ci!s ini*ly inec+i"us $-r+icles -ll le-! +" c"nsi!er-+i"n " - nucleic -ci! *en"e+-+ !e<nes s+r-in &irulence -n! u+-bili+y.21

" +":

outes of Infection and &pecies "etermine Prolonged

'atency

'-ny !ec-!es " "r -&e s"n +-+ e&en in+r-cerebr-l (ic) in"cul-+i"ns " s$ecies-!-$+e! -*en+s yiel! &ery l"n* incub-+i"n +ies +" !ise-se.

ese +y$ic-lly r-n*e r" 100 ! +" 500 ! in r"!en+s inec+e! i+ !ieren+JI -n! scr-$ie s+r-ins.22 e incub-+i"n +ie !e$en!s "n +e -*en+Os&irulence "r +e s$ecies in"cul-+e!. @-s+ers r-+s ice *uine- $i*s -n!$ri-+es -&e !ieren+ iune re$er+"ires +-+ -ec+ -*en+ s$re-! -n!$-+"l"*y -s -s been s"n by $-ss-*e " s$"r-!ic JI (sJI) -*en+s in+ese !ieren+ s$ecies23 (&i!e inr-). Peri$er-l inec+i"ns by in+r-$eri+"ne-lin+r-&-scul-r -n! "r-l r"u+es (+e "s+ n-+ur-l) c-n +-e -n e&en l"n*er +ie+" $r"!uce !ise-se +-n +e ic r"u+e e&en i+ - &irulen+ -*en+ +-+ isC-s+D "r - *i&en s$ecies suc -s 263L scr-$ie +-+ ic ills -s+ers in 65

!. Me*-r!less " r"u+e -s l-+er !e+-ile! l-+ency is l-r*ely b-se! "n "s+rec"*ni+i"n -n! su$$ressi"n " - "rei*n -*en+ +-+ !ells in -n! !eri&esr" +e en&ir"nen+.Kr-l -!inis+r-+i"n " +e 263L scr-$ie -*en+ in -s+ers c-n yiel!$r"l"n*e! -sy$+"-+ic incub-+i"n +ies ye+ s+ill le-! +" le+-l !ise-see&en en -!inis+ere! r" "l! s"il s-$les +e c""n s"urce "c"n+inu"us en!eic scr-$ie in EL -n! =cel-n!ic see$.2425 Kn +e "+er -n!re$e-+e! i* "r-l !"sin* " ice i+ +e &irulen+ #si-+ic HEJI -*en+ -ils+" $r"!uce !ise-se i+in +e n"r-l "use lies$-n.26 us ice c-nsu$$ress -n!%"r eliin-+e +is -*en+ $eri$er-lly. =n u-ns -sy$+"-+icinec+i"ns c-n be -s l"n* -s 5–30 y r" +e +ie " eG$"sure -s es+-blise!in uru27 -+er $eri$er-l in"cul-+i"ns " sJI c"n+-in-+e! *r"+ "r"ne

-n! in +e e$i!eic s$re-! " +e -*en+ +" "" -ni-ls -n! u-ns(&JI) &i- c"n+-in-+e! ee!. # curren+ unc"n+r"lle! " cer&i!s (I)c"n+inues +" s$re-! *e"*r-$ic-lly -cr"ss +e Eni+e! +-+es +" il! !eer -n!el. e en&ir"nen+-l s"urce " inec+i"n is cle-r in -ll +ese -F"r inec+i"ns. Knly in sJI - rel-+i&ely r-re -n! -&irulen+ is +een&ir"nen+-l s"urce n"+ "b&i"us. @ence sJI is - s$"r-!ic bu+ n"+necess-rily Cs$"n+-ne"usD inec+i"n.28

" rel-+e! $r"bles ur+er c"nr"n+ -n Cinec+i"us PrPresD. Hirs+ "r-l!"sin* eG$erien+s s" +-+ +e inec+i"us -*en+ bu+ n"+ PrPres sur&i&es


























+e !i*es+i&e Fuices.2930 #*en+ bu+ n"+ PrP sur&i&-l is n" ur+ersubs+-n+i-+e! by $r"+ein-se L (PL) !i*es+i"ns +-+ !es+r"y -ll "rs " PrPinclu!in* +e rel-+i&ely PL resis+-n+ Cinec+i"usD PrPres "r.31 '"re"&eri* le&els " inec+i"us -*en+ -re Au-n+i+-+i&ely rec"&ere! r" !i*es+e!br-in e&en -+er 3 l"*s " PrP -n! PrPres -re !es+r"ye!. is "ul!l"*ic-lly le-! +" -n eG-in-+i"n " n"nPrP -*en+ c"$"nen+s es$eci-lly

"lecules -n! &ir-l s+ruc+ures bes+ !esi*ne! +" inec+ --ls &i- +e "r-lr"u+e. ese inclu!e &iruses i+ +eir $r"+ec+e! nucleic -ci!s +-+ -re $-r+" +e &-s+ e+-*en"e. ('e+-*en"e32 reers +" $re&i"usly unn"nc"uni+ies " icr"bi-l "r*-niss in +e en&ir"nen+ +-+ -re bein*!isc"&ere! usin* *ene+ic seAuencin* r-+er +-n l-b"r-+"ry cul+i&-+i"n.) esec"n! c"nun!ru r-ise! by $r"l"n*e! $eri$er-l l-+ency is " -ny "r "PrP "r - s$"n+-ne"us PrPres see! c-n "!ul-+e i+s "n Auiescence in -+issue s$eci<c -y -n! +en su!!enly rele-se i+sel +" unce-sin*ly re$lic-+ei+ - s+r-ins$eci<c !"ublin* +ie in br-in.33 @"s+ c"n+r"ls " - "rei*nen&ir"nen+-l -*en+ "ul! +y$ic-lly be in&"l&e! in +is +y$e " $-++ern." +":

&ilent eplication of T&% Agents with 'ate !nset PrP-

res

ie c"urse -n-lyses " inec+i&i+y +i+ers -n! PrP c"n&ersi"n -+er br-inin"cul-+i"n !e"ns+r-+e - clinic-lly silen+ $-se " eG$"nen+i-l -*en+re$lic-+i"n +-+ s+-r+s ell be"re l-+e"nse+ PrPres $-+"l"*y. =n $-r+icul-rsuc s+u!ies s" y PrPres is - $""r subs+i+u+e "r Au-n+i+-+i&ely-ssessin* -*en+ re$lic-+i"n. Hi*ure 1 s"s eG$erien+-l !-+- "r sJI in-s+ers34 - s$ecies +-+ is Aui+e susce$+ible +" +is u-n -*en+. =n-s+ers sJI c-uses i!es$re-! br-in lesi"ns 120 ! -+er ic in"cul-+i"n

ere-s + ice i+ sJI -&e - 360 ! l-+ency i+ &ery lii+e! lesi"ns.3536

=n +e !-+- " Hi*ure 1 +ere is - cle-r !isc"nnec+ be+een +e +ie -n!sl"$es " -ccuul-+in* -*en+ (s"li! re! line) &s. +"se " PrPres (blue br"enline). >"+e +e $r"*ressi&e l"* -ccuul-+i"n " inec+i"us $-r+icles s+-r+in* -+20 ! un+il - -Gi-l inec+i&i+y is re-ce! -+ 90 !. #*en+ -ccuul-+i"n is+en -rres+e! -n! re-ins -+ - $l-+e-u -s clinic-l si*ns be*in. "r+ly be"re-*en+ -rres+ -+ 90 ! PrPres be*ins +" "r -n! -Gi-l PrPres (65Q " +e+"+-l br-in PrP) r-$i!ly c"inci!es i+ -*en+ -rres+. =n +e c-se " PrPres+ere is -n "bser&-ble 2 l"* rise (r" 0.6 -+ 80 ! +" 60Q). e PrPres s"s-n i!en+ic-l slee$ sl"$e en $l"++e! "n - l"* sc-le "r e&en eG+r-$"l-+e! +"- le&el " PrPres +-+ is n"+ !irec+ly !e+ec+-ble. '"s+ si$ly: (1) PrPres-$$e-rs -s - l-+e res$"nse +" i* le&els " +e inec+i"us -*en+ -n! (2) i*

PrPres c-n -c+ -s $-r+ " -n inn-+e iune res$"nse +-+ lii+s -*en+re$lic-+i"n -n!%"r sur&i&-l. r-$$in* " inec+i"us $-r+icles in - PrPres-yl"i!37 c-n be "ne un!erlyin* ec-nis "r +is -rres+ (see +e sec+i"nCPrP is - MeAuire! ell in!in* i+e "r =nec+i"us P-r+iclesD).






























Figure 1. @-s+er sJI $r"*ressi"n in !-ys $"s+inec+i"n ic. u$eri$"se!!-+- "r inec+i"us +i+er in l"*s (re! s"li! line) -n! Q PrPres " +e +"+-l PrP(blue br"en line). PrP is n"+ c"n&er+e! +" PrPres un+il 80 ! -n! PrPress"s - l-+e ..." +":

PrP-res $on7ersion Progresses at a ate ,ery "ifferent

from Agent

Hi*ure 1 -ls" !e"ns+r-+es -+e-+ic-lly i$"r+-n+ !-+- +-+ -ll"s "ne +"c-lcul-+e -n! c"$-re +e !"ublin* +ies " -*en+ -n! PrPres c"n&ersi"n.

e eec+i&e ("bser&e!) !"ublin* +ie (+i) by !e<ni+i"n inc"r$"r-+es b"+re$lic-+i"n -n! eliin-+i"n34 -n! c-n be -$$lie! +" - "lecule -s ell -s -ninec+i"us $-r+icle. e sJI !"ublin* +i in -s+ers is 7.6 !. =n -re!c"n+r-s+ en c-lcul-+e! by +is eAu-+i"n +e +i " PrPres in Hi*ure 1 is0.116 ! "r R65S *re-+er +-n +e -*en+ r-+e - cle-rly se$-r-+e $r"cess.

is "bser&-+i"n uni<es -ny !i&erse b-c+eri-l ye-s+ -n! $r"+ein-**re*-+i"n $en"en- bec-use siil-r +y$es " $r"+ein is"l!in* c-n$r"*ress r-$i!ly e&en en ini+i-+e! by !ieren+ +y$es " $-s+ -n!cuul-+i&e en&ir"nen+-l s+resses. ese inclu!e +e -ny +"Gic ceic-ls+re-+en+s +-+ in!uce in+r-cellul-r ye-s+ $r"+ein -**re*-+es38 in -!!i+i"n +"+e -n! c"n&en+i"n-l &ir-l inec+i"us -*en+s +-+ ul+i-+ely in!uce PrPres -n! neur"<brill-ry +-n*le "r-+i"n res$ec+i&ely in n"n!i&i!in*--li-n neur"ns.39

Iisc"r!-n+ r-+es " -*en+ re$lic-+i"n -n! PrPres c"n&ersi"n -re -c"nsis+en+ e-+ure " s in + -ni-ls. is !isc"r!-nce -s n"+ been"b&i"us in +e &ery s"r+ incub-+i"n 263L -s+er scr-$ie ic "!el (65 ! +"+erin-l si*ns). @"e&er -!!i+i"n-l "!els i+ incub-+i"n +ies " R110 !

-ll !e"ns+r-+e - $r"*ressi&e sl" eG$"nen+i-l rise in inec+i&i+y "ll"e! by- su!!en incre-se in PrPres -s s"n in Hi*ure 2 " #si-+ic HEJI - s+r-in+-+ is uc "re &irulen+ "r + ice +-n sJI. e HEJI -*en+ s+e-!ilyre$lic-+es by R4 l"*s (r" 20 +" 90 !) be"re $r"&"in* - su!!en r-$i!rise " PrPres in +e br-in.40 >"+e +-+ +"+-l PrP (le+ $-nel) re-ins c"ns+-n+-s i+s !eri&-+i&e PrPres is bein* is"l!e! (TPL l-nes) i.e. PrPres is"l!in*is - $r"cess " c"n&ersi"n r-+er +-n +rue re$lic-+i"n. '"re"&er - neeG+reely -s+ I -*en+ "!el in b-n &"les ic +-es "nly 35 ! +"+erin-l !ise-se41 -ls" s"s - -re! !iscre$-ncy be+een PrPres -n!inec+i"us +i+er. ese !ise-se! br-ins -&e i* le&els " inec+i&i+y (8.4l"*s%*) bu+ "nly l" le&els " PrPres. " eG$l-in +is i+ is y$"+esie! +-+(1) +ere -re !ieren+ +"Gic -n! inec+i"us PrPres "rs (2) +ese PrP "rs

re$lic-+e -n! -+ure -+ !ieren+ r-+es -n! (3) +e inec+i"us PrPres subse+c"n+-ins -!!i+i"n-l uniAue is"l!e! &-ri-n+s +-+ enc"!e -ll +e -s+ -n!sl" I s+r-ins in +ese &"les. >"+-bly b-n &"les -&e rele&-n+ -++ribu+esbey"n! PrP. K $-r+icul-r in+eres+ is +eir susce$+ibili+y +" -ny !ieren+ &ir-linec+i"ns -n! +eir -bili+y +" -c+ -s &ir-l reser&"irs in ""n"+ic inec+i"ns. 42

ese &iruses -y en-nce +e &irulence " s"e I s+r-ins -s !"re+r"&iruses "r I inec+i"n in "+er r"!en+ cells (re&iee! in re. 21). =+ is-ls" $"ssible +-+ &"les c-rry s"e s+r-ins -sy$+"-+ic-lly -n! s$re-!

s +r"u* +e en&ir"nen+ &i- eGcreen+ -s +ey !" "r "+er &iruses.

























e ""n"+ic s$re-! " s is n"+ ell s+u!ie! -n! c"nce$+s -n!$re&en+i"n -y be r-!ic-lly +r-ns"re! by e+-*en"ic -n-lyses.

Figure 2. ,-+e "nse+ " PrPres in HEJI + ice illus+r-+es c"ns+-n+ le&el "PrP in le+ $-nel i+"u+ $r"+ein-se L (PL) r" 50–130 !. Mi*+ $-nel s"s+e HEJI -*en+ re$lic-+es by 5 l"*s in +ese ice be"re PrPres is <rs+!e+ec+-ble ..." +":

Agent-Induced Neurodegeneration "oes Not e9uire

PrP-res

'-re! neur"!e*ener-+i&e c-n*es c-n be ini+i-+e! by - -*en+ i+"u+$-+"l"*ic-l PrPres -s -n -cc"$lice. is is ell !e"ns+r-+e! by +e &ery$r"l"n*e! sJI r-+ "!el. M-+s inec+e! ic i+ sJI -&e -n incub-+i"n +ie" R350 ! &s. -n incub-+i"n " 120 ! in -s+er sJI. Me-r-bly in +esesJI inec+e! r-+s cl-ssic-l s$"n*i"r br-in c-n*es -n! i!es$re-!icr"*li-l -c+i&-+i"n bec"e $r"inen+ siul+-ne"usly -s uc -s 100 !be"re PrPres -es i+s en+r-nce.23 =+ is "+en -ssue! +-+ PrPres is +ec-use " neur"n-l !e-+ in s bu+ +ese resul+s s" +-+ +e sJI -*en+i+sel c-n $r"&"e -c+i&e s$"n*i"r neur"!e*ener-+i"n i+"u+ -$$reci-blePrPres $r"b-bly e!i-+e! in $-r+ by icr"*li-. is +y$e " !-+- -es i+cri+ic-l +" c"nsi!er e-rly +er-$eu+ic in+er&en+i"ns -*-ins+ +e -*en+r-+er +-n "cusin* s"lely "n inibi+in* l-+es+-*e PrPres "r-+i"n." +":

A ole for PrP In %liminating Infectious Particles: with

Pathologic &e9uelae

e $re!ic+i"n +-+ "s+ PrPres c-n el$ lii+ inec+i"n -s been &eri<e! byrecen+ cul+ure eG$erien+s. #+ &ery e-rly $-ss-*es -+er inec+i"n "neur"n-l 1 cells i* PrPres le&els c"inci!e i+ lii+in* uru -*en+-ccuul-+i"n. "n&ersely - !el-ye! l" le&el " PrPres +"ler-+es - 1000"l!i*er +i+er " +e HEJI -*en+.33 #n e&en "re !r--+ic !e"ns+r-+i"n +-+PrPres c-n unc+i"n +" eliin-+e i* le&els " -*en+ -s n" been

!e"ns+r-+e! in s+-+i"n-ry r-+ neur"n-l cell cul+ures inec+e! i+ HEJI.H"ur l"*s " inec+i"us -*en+ ere eliin-+e! r" cells !urin* - c"n+inuin*en"r"us incre-se in +e $r"!uc+i"n " b"+ PrP -n! PrPres.39 is <n!in* isc"n+r-ry +" +e $ri"n eG$ec+-+i"n +-+ PrPres ill incre-se +e inec+i"us +i+er.Hur+er"re +is n"ninec+i"us PrPres sel$er$e+u-+es un!ersc"rin* -s+ress res$"nse -in +" +e s+ress in!uce! b-c+eri-l el-b"r-+i"n " bi"<l-yl"i!s43 -s ell -s +" ye-s+ $r"+ein -**re*-+es in!uce! by en&ir"nen+-lceic-ls.38 el$r"$-*-+in* PrPres in +e cure! r-+ neur"ns is cle-rly -n




















s+resses $r"&"e +eir recru!escence -n! !issein-+i"n. is $-++ern <+s +e10–30 y !"r-ncy -n! recru!escence " b"+ i-+r"*enic sJI -n! uru-*en+s in u-ns. is $r"cess is -ls" -$$-ren+ in +e uc s"r+er HEJI"use "!el in "ur res$ec+s. Hirs+ is"l-+e! br-in icr"*li- - rel-+i&e "$eri$er-l i*r-+"ry !en!ri+ic cells c"n+-in eG+reely i* le&els " +e HEJI -*en+ bu+ inu+e -"un+s " PrP -n! n" !e+ec+-ble PrPres (re&iee! in

re. 11). ec"n! -rr-y s+u!ies " rele&-n+ "lecul-r -rers !e"ns+r-+e!inn-+e iune res$"nses in inec+e! bu+ n"+ c"n+r"l icr"*li-. '"re"&er+is s$eci<c *r"u$ " yel"i! cell +r-nscri$+s -re subs+-n+i-lly ele&-+e! in HEJI inec+e! icr"*li- bu+ -re n"+ e!uce! by PrPres.51 ir! s"e " +eseinn-+e iune +r-nscri$+s -re $r"&"e! !urin* +e e-rlies+ $-se "eG$"nen+i-l -*en+ re$lic-+i"n ell be"re PrPres "r neur"!e*ener-+i&ec-n*es be*in.40 ese inn-+e iune -rers cle-rly si*niy "s+rec"*ni+i"n " - "rei*n inec+i"us $-r+icle r-+er +-n "s+ PrPres.ubseAuen+ s+u!ies -&e unc"&ere! -!!i+i"n-l i$"r+-n+ e-rly "s+ inn-+eiune res$"nses in scr-$ie52 !e"ns+r-+in* +ese res$"nses -re - *ener-le-+ure " inec+i"ns. H"ur+ i* scr-$ie inec+i"us +i+ers -&e been"un! in is"l-+e! $eri$er-l $l-s-cy+"i! !en!ri+ic cells +-+ l-c -ny

!e+ec+-ble PrP.53 is ur+er eG+en!s +e cen+r-li+y " +ese +y$es " cells in -*en+ l-+ency -n! +issue s$re-!. =+ -ls" su**es+s +-+ PrP -y n"+ be -nessen+i-l "r in+e*r-l c"$"nen+ " +e ini-l inec+i"us $-r+icle. =+ is -ls"uncle-r " PrPres - see! "r i+s "n c"n&ersi"n c"ul! -rres+ i+sel "rye-rs -n! +en re-c+i&-+e by see!in* i+sel in s$eci-lie! !en!ri+ic cells +-+c"n+-in n" !e+ec+-ble PrP." +":

Proof That an AnimalKs Innate Immune (iochemical

&ystems 'imit Agent %8pansion

e -b"&e "bser&-+i"ns s+r"n*ly i$lic-+e c"$leG cellul-r res$"nses +" -"rei*n -*en+ +-+ -re unrel-+e! +" ei+er PrP "r PrPres c"n&ersi"n. =+ -sl"n* been n"n +-+ PrP i+sel is insuBcien+ +" -e cells susce$+ible +"inec+i"n since -n -ni-lOs lun* -n! i!ney e$i+eli-l cells i+ PrP !" n"+n"r-lly bec"e inec+e!. us in!i&i!u-l cell -n! c"$leG -ni-l res$"nses-re in&"l&e!. e cri+ic-l r"le " -n -ni-lOs cellul-r !eense ec-niss-*-ins+ -*en+s -s n" been c"nclusi&ely !e"ns+r-+e!. -sic-lly en*r"n in cul+ure -*en+s -re rele-se! r" ul+icellul-r su$$ressi&e "s+c"n+r"ls. us -*en+s -re ree! +" re$lic-+e r-$i!ly -n! s"e -*en+s -sHEJI -cie&e e&en i*er +i+ers $er cell +-n in br-in. "n&ersely en+ese cul+ure! -*en+s -re rein"cul-+e! ic +ey c-n n" l"n*er re$lic-+e

r-$i!ly i.e. +ey -re -*-in c"ns+r-ine! by c"$leG "s+ c"n+r"ls +-+ c-n+-r*e+ b"+ re$lic-+i"n -n! !es+ruc+i&e $r"cesses. Hi&e &ery !ieren+ scr-$ie-n! u-n -*en+s i+ i!ely !i&erse + i eec+i&e !"ublin* +ies r"4.3 +" 32 ! in + ice -ll su!!enly -n! !r--+ic-lly re!uce! +eir !"ublin*+ie +" - +i " 1 ! en *r"n in 1 neur"n-l cells.33 us -ll +ese !ieren+

-*en+s -re c-$-ble " r-$i! re$lic-+i"n en rele-se! r" ul+icellul-r"s+ c"n+r"ls. M-$i! -*en+ re$lic-+i"n !i! n"+ !e$en! "n PrPres-ccuul-+i"ns bec-use PrPres in cul+ure s$-nne! r" 0Q +" 50Q. enr-$i!ly re$lic-+in* JI -n! scr-$ie -*en+s in cul+ure ere rein"cul-+e! in

















ice +ey recre-+e! +eir s+r-ins$eci<c re*i"n-l neur"$-+"l"*y in -!!i+i"n+" +eir "ri*in-l !is+inc+i&e l"n* l-+encies.5455 us +e re$lic-+i"n -n! sur&i&-l" +ese -*en+s -re cle-rly lii+e! by cells -n! -c+"rs n"+ $resen+ in"n"+y$ic cul+ure. is !-+- s"s n" e&i!ence "r -*en+ u+-+i"ns -s +ec-use " +is c-n*e. '"re"&er ice cle-rly c-n res$"n! +" -n!!ieren+i-lly re+-r! e-c " +ese -*en+s.

#+ - sin*le cell le&el inn-+e iuni+y -ls" -es cells $erissi&e "r$-r+icul-r -*en+s. -n! e&en cells in cul+ure +-+ syn+esie i* le&els """l"*"us PrP c-n resis+ inec+i"n "r unn"n re-s"ns. >eur"bl-s+"-(>2-) +u"r cells use! "r -ny scr-$ie s+u!ies -re n"n +" be *ene+ic-llyuns+-ble -n! ine&i+-ble $r"*ressi&e $"$ul-+i"n &-ri-n+s -re !ieren+i-llyrece$+i&e +" e&en - sin*le -*en+ s+r-in suc -s 22, scr-$ie. 56 @ence i+ ill beuncle-r i re$lic-+i"n "r l"ss " - *i&en -*en+ is !ue +" -l+ere! cellc-r-c+eris+ics "r u+-n+ s+r-ins. e $"si+i&e inec+i"n " *ene+ic-lly s+-ble1 cells i+ &ery !ieren+ -*en+s -ll"e! us +" !e"ns+r-+es +-+ +esecells eG &i&" c-n !ieren+i-lly rec"*nie -n! su$$ress +ese -*en+s +"u*+eir inn-+e iune ne+"rs. 1 cells i+ +eir in&-ri-n+ PrP -n! cell$en"+y$e cle-rly s" in+rinsic $reerences "r $-r+icul-r -*en+s. 22

ince 1 cells -re $erissi&e "r inec+i"n by -ll +ese -*en+s +ey !" n"+reAuire -!!i+i"n-l -c+"rs. =ns+e-! i+ is e&i!en+ +-n -c+i&e cellul-r $r"cessc-n lii+ inec+i"n -n! e&en le-! +" - $r"*ressi&e cure. H"r eG-$le +eurine -!-$+e! uru -*en+ re$r"!ucibly -n! s+-bly re$lic-+es "r R1 y -+ -c"ns+-n+ le&el -n! c"n+inues +" elici+ l-r*e -"un+s " PrPres. We+ -s n"+e!+is -*en+ -++-ins -n inec+i"us +i+er +-+ is "nly 1%1000+ " +e urine-!-$+e! HEJI -*en+.33 '"re"&er urine -!-$+e! &JI is -ble +" inec+$-r-llel 1 cells -n! in!uce &JIs$eci<c PrPres b-n!s "r 9 $-ss-*es (3–4 ees). @"e&er in +is c-se PrPres !iinises "&er +e neG+ e ees-n! ul+i-+ely is un!e+ec+-ble (i+ n" c-n*e in +e +"+-l cell PrP). issu**es+s +ese 1 cells -&e subs+-n+i-lly cure! +esel&es " +e &JI-*en+. e -&e re$e-+e! +is "bser&-+i"n R5 +ies usin* !ieren+ &JIinec+e! "use br-in s-$les -n! !ieren+ $-ss-*es " 1 cells (,iu

i++-n Li$"rir "+si"s -n! '-nueli!is un$ublise! !-+-). le-rly +is-*en+ re!uc+i"n (-ls" s"n by - re$resen+-+i&e inec+i"us -ss-y) in&"l&es -n-c+i&e inn-+e !eense $r"cess +-+ is -*en+s$eci<c r-+er +-n - l-c "s"e -c+"r necess-ry "r inec+i"n. "e " +ese !ieren+i-l in+rinsic cellc"n+r"ls -y be unc"&ere! by i* +r"u*$u+ M># in+ererence screens.=n!ee! ini+i-+i&es +-+ +-r*e+ +ese n"nPrP -c+"rs s"ul! be " &-lue in-rres+in* -n! +re-+in* JI." +":

PrP is a e9uired $ell (inding &ite for Infectious T&%

Particles

PrP is - P= -nc"re! $r"+ein -n! is ul+r-s+ruc+ur-lly -bun!-n+ "n $l-s- -n!M ebr-nes.45 ile "+er ebr-ne "lecules -n! cellul-r -cinery-re liely +" !ri&e PrPres -ccuul-+i"n in +e li&in* cell i+ is cle-r r" PrPn"c"u+ s+u!ies +-+ "s+ PrP is essen+i-l "r $r"*ressi&e scr-$ie -*en+inec+i"n.57 Kne in+er$re+-+i"n " +ese !-+- $"si+s +-+ s"e "r " PrPus+ be +e inec+i"us -*en+. #l+ern-+i&ely "s+ PrP c-n be - rece$+"r -n!%"r




















sc-"l! reAuire! "r -c+i&e -*en+ re$lic-+i"n -n! s$re-!. is l-++er &ie isb-se! "n es+-blise! &ir-l reAuireen+s "r - $-r+icul-r "s+ $r"+ein eree&en - sin*le c"!in* u+-+i"n in +e "s+ rece$+"r c-n $re&en+inec+i"n.47 Hi*ure 3# !i-*r-s +e PrP null s+-+e en +ere is n" sc-"l! "reec+i&e -*en+ re$lic-+i"n. @ence -*en+ $-r+icles !isin+e*r-+e -n! -reeliin-+e!. Hi*ure 3 s"s inec+i"n i+ +" !ieren+ inec+i"us

-*en+s e-c in!ucin* - rec"*ni-bly !ieren+ PrPres -yl"i! -**re*-+e. =nHi*ure 3 se$-r-+e $r"cesses " -*en+ re$lic-+i"n -n! PrPres -**re*-+i"n-re !i-*r-e! inclu!in* +r-$$in* " s"e -*en+ by PrP -yl"i!. ile+ere is - cle-r !is+inc+i"n be+een +e inec+i"us -n! +e $urely *ene+icc-uses " PrP $-+"l"*y b"+ c-n in!uce +r-nsebr-ne "rs " PrP +-+le-! +" lys"s"-l $r"cessin* -n! -yl"i! $l-Aue !e$"si+i"n.58

Figure 3. '"!el " in&-!in* 25 n &ir-l $-r+icle bin!in* i+s reAuire!

"s+ PrP rece$+"r +" in!uce PrPres -yl"i!. ( A) "s !isin+e*r-+i"n -n!eliin-+i"n " +e inec+i"us $-r+icle i+ i+s nucleic -ci! c"re (s"li! circle)-n! $r"+ec+i&e ...'"s+ s+r-ins (-s s+r-in #) in!uce -n i!en+ic-l PrPres b-n! $-++ern $r"&i!e!+-+ +e cell +y$e -n! s$ecies -re n"+ &-rie!. =n !ieren+ s$ecies -n! cell+y$es +e PrP b-n! !ierences -re l-r*ely !ue +" $"s++r-nsl-+i"n-l*lyc"syl-+i"n -n! !e*lyc"syl-+i"n i+ neur-ini!-se re&e-ls +e un!erlyin*""*enei+y " PrP <rs+ s"n by res"lu+i"n " - sin*le !iscre+e is"elec+rics$"+ in 2I *els.59 &en "re eG+ensi&e !e*lyc"syl-+i"n +-+ ur+er iniiesPrP &-ri-+i"n !"es n"+ re!uce inec+i&i+y "r -l+er +e s+r-inOs l-+ency -n!neur"$-+"l"*ic $en"+y$e.37 >e&er+eless e -! $r"$"se! +-+ - r-re "runusu-l -*en+ (s+r-in ) i*+ bin! PrP !ieren+ly +" yiel! - &-ri-n+ PrPres

b-n! $-++ern +-+ is -in+-ine! in &-ri"us s$ecies -n! cell +y$es re*-r!less" *lyc"syl-+i"n !ierences.47 is -s n" been &eri<e! eG$erien+-lly. ePrPres !"uble+ in!uce! by +e uniAue %&JI -*en+ is c"ns+-n+ in inec+e!c"s u-ns + ice -n! e&en in "n"+y$ic cell cul+ures. 22 =n c"n+r-s+"s+ "+er JI -n! scr-$ie s+r-ins -&e n" been c"nclusi&ely s"n +"in!uce in!is+in*uis-ble PrPres b-n!s in s+-n!-r! + "use br-ins.36 isin&i+es ur+er Aues+i"ns "r $ri"n $r"$"nen+s -b"u+ -+ "bser&-ble PrP!ierences i*+ enc"!e s+r-ins.# PrP rece$+"r "!el <+s -ny i$"r+-n+ e-+ures inclu!in* +e s$eciesC+r-nsissi"n b-rrierD line! +" "s+ PrP c"!"n u+-+i"ns. =+ -ls" -cc"un+s "r+e -b"&e re+rie&-l " - bi"l"*ic-lly i!en+ic-l -*en+ r" cells i+!ieren+ PrPres b-n!s -n! PrP *lyc"syl-+i"n $-++erns. PrPres $-++erns -re

&ery !ieren+ in ly$"i! +issues br-in -n! cul+ure! cells bu+ -ll +ese cellsyiel! +e s-e -*en+ r-+er +-n in!i&i!u-lly !is+inc+ s+r-ins. #cc"r!in* +" +e$ri"n c"nce$+ -+ le-s+ s"e " +ese !ieren+ PrP "rs s"ul! enc"!e&-ri"us s+r-ins. Ies$i+e in+ense e"r+s nei+er - re$r"!ucibly inec+i"usn"r - s+r-inenc"!in* PrP c"n"rer -s been i!en+i<e!. =n su !ieren+-*en+ s+r-ins *i&e +e s-e PrPres $-++ern -n! s-$les i+ &ery !ieren+PrPres $-++erns e&en r" !ieren+ s$ecies c-n $r"$-*-+e +e s-einec+i"us -*en+.

























e c"nce$+ +-+ PrP is - reAuire! -*en+ rece$+"r r-+er +-n +e c-us-linec+i"us -*en+ -s recei&e! li++le -++en+i"n. @"e&er recen+ s+u!ies s"+-+ PrP is in+i-+ely in&"l&e! in +e lie cycle " "+er inec+i"us -*en+s r"&iruses +" *r-ne*-+i&e b-c+eri-.6061 =n!ee! PrP is +e rece$+"r reAuire! "r- b-c+eri-l "r-l inec+i"n -n! +is <n!in* $-r-llels +e PrP reAuireen+ by

-*en+s "r inec+i"n. #n incre-se in PrP e&en en i+s seAuence !"es n"+

-+c +e PrP " +e inec+e! !"n"r -re!ly -cili+-+es inec+i"n " u-n-*en+s +" ice. =n -c+ * ice "&ereG$ressin* + urine PrP -re "resusce$+ible +" u-n &JI +-n * ice "&ereG$ressin* u-n PrP.22 is<n!in* is c"$-+ible i+ PrP -s - rece$+"r e&en i sli*+ly -e! bu+ isc"n+r-ry +" +e $ri"n !"*- +-+ PrP seAuence !ierences ill necess-rily+-r+ cr"sss$ecies inec+i"n. # &ir-l in!uc+i"n " $-+"l"*ic-l $r"+ein-**re*-+es inclu!in* u-n $-r-yG"&irus in!uce! neur"!e*ener-+i&eneur"<brill-ry +-n*les39 -ls" *i&es $rece!ence +" -*en+ in!uce! PrPres-s !"es +e nees+ !e"ns+r-+i"n +-+ - &ir-l inec+i"n c-n in!uce -c"n"r-+i"n-l C$ri"nlieD s+-+e in i+"c"n!ri-l ebr-ne c"$leGes('#V).6263 is l-s+ $-r-llel is e&en "re in+ri*uin* bec-use '#V -c+i&-+e-n! $r"$-*-+e -n+i&ir-l inn-+e iune res$"nses - <n!in* re-r-bly

c"nsis+en+ i+ +e inn-+e iune res$"nses in s re&iee! -b"&e. uc<n!in*s ur+er su$$"r+ +e "!el in Hi*ure 3 ic s"s - &ir-l$-r+icle +-+ in!uces PrPres -**re*-+i"n by bin!in* i+s reAuire! "s+rece$+"r.47

" +":

The 3unction<s= and 'ocation of PrP are Ad7antageous

for T&% Agents

#l+"u* i+ is "+en s+-+e! +-+ +e n"r-l unc+i"n " PrP is unn"n PrP is

cle-rly in&"l&e! in +erin-l neur-l !ieren+i-+i"n cell+"cell c"n+-c+s -n!syn-$se "r-+i"n (re&iee! in re. 39). >ely "re! n-n"+ubes $r"lier-+e-s PrP is in!uce! in cul+ure! neur"ns un!er*"in* +erin-l !ieren+i-+i"n -n!n-n"+ubes -cili+-+e +e +r-nsissi"n " &iruses. =n!ee! +e $r"lier-+i"n "PrP ric n-n"+ubes resul+ in R120"l! incre-ses in inec+i"us $-r+icles$er cell.39 ec-use PrP is n"+ essen+i-l "r +e n"r-l unc+i"n " -n -ni-l

-*en+ bin!in* +" "s+ PrP es$eci-lly -+ l"er -sy$+"-+ic le&els illn"+ resul+ in l"ss " -ny cri+ic-l $ysi"l"*ic-l unc+i"n. #*en+ iF-cin* " PrP+us $r"&i!es "r l"n*+er sur&i&-l " b"+ +e -*en+ -n! +e -ni-l. enPrP bin!s +e inec+i"us $-r+icle i+ c-n -ls" el$ +e -*en+ i!e r" -!-$+i&eiune sur&eill-nce. #!!i+i"n-lly PrPres -yl"i! +r-$$in* in yel"i!!en!ri+ic cells26 -n! -cr"$-*es c-n s+ruc+ur-lly $r"+ec+ +e -*en+ r"

eliin-+i"n "r -ny ye-rs $-r+icul-rly bec-use PrPres -s "+er -yl"i!s-re s" i$ene+r-ble -n! ins"luble. Hin-lly -$$"se! $l-s- ebr-nesbe+een +" cells -re n"n +" eGc-n*e "lecul-r c"$"nen+s -n! +us-*en+ -++-cen+ +" PrP ill ur+er -cili+-+e cell+"cell s$re-! +e i*ly-&"re! r"u+e "r -*en+s.55 K+er PrP unc+i"ns -y c"ner -!!i+i"n-l-!&-n+-*es." +":

































T&% Infections with 6 &trains &hare 3eatures with 2east

LPrionsM

Hi*ure 3 -ls" $re!ic+s +-+ +" !ieren+ -*en+ s+r-ins e-c in!ucin*rec"*ni-bly uniAue $-+"l"*ic-l PrPres b-n!s c"ul! eGis+ in +e s-e cell.=n +e $ri"n "!el i+ is cl-ie! +-+ -n in+ere!i-+e PrPres cier- (" +"!ieren+ PrP c"n"rers) ill -+eri-lie -n! *i&e rise +" in+ere!i-+einec+i"us $r"$er+ies -s $r"$"se! "r -!-$+i&e cr"sss$ecies PrPresc"n&ersi"ns.28 =n c"n+r-s+ in +e Hi*ure 3 &ir-l "!el +" !ieren+ -*en+s "ul! c"n+inue +" in!uce in!e$en!en+ # -n! "rs " PrPres i.e.+" inec+in* s+r-ins "ul! -in+-in +eir in!e$en!en+ i!en+i+ies -n! e-cPrPres "ul! c"n+inue +" see! i+sel -n! -ccuul-+e in +e cell. =n -c+ +"JI s+r-ins -&e been s"n +" siul+-ne"usly re$lic-+e in -ni-ls "r 400 !-n! e-c -in+-ins i+s "ri*in-l s+r-in $en"+y$e.11 '"re"&er +" !ieren+-*en+s in!ucin* +" !ieren+ PrPres c"n"rers c-n -ccuul-+e in - 1cell i+ n" e&i!ence "r -ny cieric PrPres in+ere!i-+e.55 is l-++er

"bser&-+i"n $-r-llels ye-s+ C$ri"nD -yl"i! s+u!ies +-+ -ls" s" +"!ieren+ +y$es " $r"+ein -**re*-+es c-n eGis+ in +e s-e cell. =n ye-s+ cells+ese !ieren+ cy+"$l-sic -**re*-+es -re iGe! by -seGu-l -+in* - n"n'en!eli-n *ene+ic $r"cess38 &ery !ieren+ r" inec+i"ns " --ls i++issues$eci<c -*en+ +-r*e+in* -n! s$re-!. Kn +e "+er -n! i "ne i*n"res+e Cinec+i"usD !esi*n-+i"n "r ye-s+ $ri"ns b"+ ye-s+ -n! --li-n-yl"i!s s" - s+riin* -bili+y +" sel$r"$-*-+e +eir in!i&i!u-lc"n"r-+i"ns $"ssibly by usin* - siil-r ne+"r " cell $-+-ys -n!ec-niss.=n+eres+in*ly !ieren+ +y$es " ye-s+ $r"+ein -**re*-+es c-n $r""+e "rinibi+ e-c "+erOs -$$e-r-nce -n! -in+en-nce.64 =n c"n+r-s+ -n inibi+in*

inec+i"us -*en+ bu+ n"+ PrPres -**re*-+es is reAuire! +" $re&en+

su$erinec+i"n by - sec"n! -*en+.55

is is rele&-n+ "r u-n inec+i"nsbec-use &-ccin-+i"n " ice i+ l" le&els " +e -&irulen+ sJI -*en+ c-nc"$le+ely $re&en+ su$erinec+i"n by +e "re &irulen+ HEJI s+r-in i+"u++e $r"!uc+i"n " -ny !e+ec+-ble PrPres (re&iee! in re. 11). e $resence "!ieren+ +y$es " !i-*n"s+ic -yl"i! in - cell -s -!!i+i"n-l rele&-nce "ru-n !ise-se. #yl"i!s n"+ line! +" - n"n inec+i"us s"urce c-n c"eGis+i+ +"se $r"&"e! by - -*en+. P"si+i&e seri-l +r-nsissi"n " sJI +"-s+ers -s "b+-ine! r" - br-in i+ -ny cl-ssic-l #I -yl"i!$l-Aues in -!!i+i"n +" s$"n*i"r c-n*es -n! PrPres +y$ic-l "r sJI('-nueli!is un$ublise! !-+-). >ei+er -yl"i! inibi+e! +e "+er." +":

&tability: %7olution: and &election of T&% Agent &trains

=n *ener-l -*en+s c-n s" - re-r-ble l-c " c-n*e e&en en$-ss-*e! +r"u* !ieren+ s$ecies. -c -*en+ s+r-in e+er u-n "rsee$ !eri&e! *i&es - c-r-c+eris+ic incub-+i"n +ie -n! neur"-n-+"ic-llesi"n $r"<le in - *i&en s$ecies.22 Hi*ure 4 is - c"$"si+e " $ublise!eG$erien+-l !-+- s"in* rele&-n+ incub-+i"n +ie e-+ures "r u-n is"l-+es in r"!en+s. Hirs+ in seAuen+i-l ic $-ss-*es +ere is - $r"*ressi&e




























re!uc+i"n in incub-+i"n +ie !en"+in* -n incre-se! -*en+ &irulence "r +ereci$ien+ s$ecies. Iurin* +is e&"l&in* -*en+ -!-$+-+i"n +e PrPres b-n!$-++ern !"es n"+ c-n*e. ese un!-en+-l -n! $r"*ressi&e -*en+ c-n*es-re c"nsis+en+ i+ n"n &ir-l -!-$+-+i"n +r"u* nucleic -ci! u+-+i"n "rselec+i"n r" - iG+ure " rel-+e! -*en+ s+r-ins.23 =n c"n+r-s+ - siil-r$r"*ressi&e -*en+ c-n*e r" $1 +" $2 is n"+ "bser&e! -+er ic in"cul-+i"n "

recPrPres -yl"i!.65 ec"n! +e s-e -*en+ in - !ieren+ s$ecies c-n*esi+s incub-+i"n (eec+i&e !"ublin*) +ie e.*. sJI in r-+s + ice (+'")*uine- $i*s (P) -n! -s+ers (@-) -s s"n in Hi*ure 4. is in!ic-+ess$eciess$eci<c !eenses "r - *i&en -*en+ -s !iscusse! -b"&e. e *r-$ " &JI in + ice -ls" !e"ns+r-+es - &ery !ieren+ incub-+i"n $-++ern r"sJI -n! -!!i+i"n-l !is+inc+i"ns -re "b&i"us i+ +e -n!ler (M',) -n! 22,scr-$ie s+r-ins in s+-n!-r! + ice.22 us e-c incub-+i"n +ie $-++ern is!e+erine! by +e -*en+ -n! n"+ by +e in&-ri-n+ urine + PrP "r in!ee!by -ny +e "+er i!en+ic-l b-c*r"un! *enes. Me-r-bly +e &JI -*en+-$$e-rs s" !"in-n+ +-+ i+ -ls" *i&es -n i!en+ic-l s+r"n* y$"+-l-ic+-r*e+in* $-++ern in ice e&en -+er l"n*+er re$lic-+i"n in c"s () "r inu-ns (&JI) i+ !ieren+ PrP seAuences.22 ir! !es$i+e *r"+ in -

e+er"l"*"us s$ecies -*en+s c-n re+-in +eir -bili+y +" inec+ +eir !"n"rs$ecies i+ +eir "ri*in-l $en"+y$e e.*. -s+er sJI +r-nsi++e! +" icebec"es &ery $r"l"n*e! ye+ e&en -+er seri-l "use $-ss-*es +is sJI-*en+ s+ill re+-ins i+s -bili+y +" ie!i-+ely re$lic-+e r-$i!ly in -s+ers (re!-rr").66 is in!ic-+es b"+ +e $reser&-+i"n " -n in&-ri-n+ s+r-ins$eci<ce-+ure -s ell -s - u+-ble e-+ure " re+-ine! (-s+er) -!-$+-+i"n. #*-inPrPres b-n! $-++erns !" n"+ reec+ +ese e-+ures.

Figure 4. "$"si+e $ublise! eG$erien+-l !-+- "r +r-nsissi"n " sJIu-n br-in +" !ieren+ s$ecies in seAuen+i-l $-ss-*es. uine- $i* (P)-s+er (@-) urine ('") -n! r-+ sJI $l"+s c"n+-in "ri*in-l !-+- r" +e<rs+ seri-l +r-nsissi"n ...# l" le&el " -*en+ nucleic -ci! u+-+i"n i+ re+en+i"n " "nly eselec+e! &-ri-n+s sees "s+ $l-usible c"nce$+s <rs+ in+r"!uce! i+ +esein-l +r-nsissi"n eG$erien+s " P-++is"n Iicins"n -n! Liberlin inscr-$ie -n! +e re-li-+i"n +-+ +ese -*en+s -&e -n Cin!e$en!en+ *en"eD(re&iee! in res. 22 37 -n! 67). l"nin* " - sin*le u+-n+ -*en+ by eG+reeen!$"in+ !ilu+i"n -s necess-ry +" "b+-in - $ure -*en+ s+r-in i+ ne*li*iblere&ersi"n. uc -n in&-ri-n+ -*en+ is eGe$li<e! by +e cl"ne! 263L -s+erscr-$ie -*en+ +-+ bec-e -&irulen+ "r ice. ere -re -ls" scr-$ie s+r-ins+-+ s" "re reAuen+ c-n*e. =n+eres+in*ly "ne scr-$ie s+r-in i+-re!ly -l+ere! +r-nsissi"n $r"$er+ies -s recen+ly been selec+e! in iceby "!iyin* +e *lyc"syl-+i"n " PrP67 - <n!in* c"nsis+en+ i+ -*en+$-r+icles +i*+ly b"un! +" -n! inuence! by "s+ rece$+"r PrP. uc bin!in*c-n -ls" in!uce -!!i+i"n-l "s+ $r"cesses in&"l&e! in -*en+ selec+i"n. ile+e -u+"rs " +is $-$er y$"+esie ul+i$le is"l!e! "rs "rCAu-sis$eciesD " inec+i"us PrP +e res"lu+i"n " +ese !ieren+ PrP "rs-s n"+ been e&i!en+. is ne scr-$ie !-+- ins+e-! -r*ues "s+


























$-rsi"ni"usly "r - u+-ble -*en+ *en"e. Hur+er"re +e l"n*es+-blise! re&ersible si+cin* be+een +e 79# -n! 139# scr-$ie -*en+$en"+y$es67 su**es+s +-+ in"r -*en+ nucleic -ci! &-ri-n+s c-n $ersis+i+ e-c &-ri-n+ c"in* +" +e "re in i+s "re -&"r-ble en&ir"nen+ "rs$ecies. =n su +ere is b"+ selec+i&e s+-bili+y -n! u+-bili+y " -*en+s+-+ irr"rs &ir-l be-&i"r -n! +e +r-nser " s+r-ins$eci<c in"r-+i"n

enc"!e! by nucleic -ci!. Enlie i+ nucleic -ci!s n" "lecul-r "!el eGis+s+" su$$"r+ - c"$-r-ble $r"+einb-se! Cin"r-+i"nD +r-nser. '"re"&er +eul+i$le c"n"rers " PrP res +-+ -re $resue! +" enc"!e -ll +e !ieren+scr-$ie -n! JI -*en+ s+r-ins $r"$-*-+e! in + ice re-in y$"+e+ic-l. >"r-s -ny s$eci<c "r c"nsis+en+ is"l!in* been i!en+i<e! +-+ *ener-lly!e<nes +e inec+i"us "r " PrP. e ul+i$le !esi*n-+i"ns "r -ll " +e!ieren+ c-$-bili+ies " $r"$"se! PrP c"n"rers c-n be in!b"**lin* e.*.+e PrPres "rs +-+ us+ enc"!e -F"r s+r-in cl-sses suc -s PrPcF! PrPscPrPc! PrP +e PrP! "r +e !ise-se "r - PrP "r +e neur"+"Gic "r-n! "s+ recen+ly - sub$"$ul-+i"n " -n inec+i"us $r"+e-se sensi+i&e PrPsens "r (re&iee! in re. 31). Per-$s +e c-$-ci+ies " PrP -re "&ers+-+e!X" +":

The &tructure of Infectious Particles

ere-s PrPres <brils -n! -yl"i! -**re*-+es !is+ribu+e "&er - u*e sies$ec+ru inec+i"us -*en+s -&e - ""*ene"us 120 sie -n! be-&e-s &ir-l $-r+icles +-+ se$-r-+e r" !is-**re*-+e! PrP.37 =nec+i"us$re$-r-+i"ns -ls" c"n+-in ul+r-s+ruc+ur-l 25 n elec+r"n !ense $-r+icles +-+!" n"+ bin! PrP -n+ib"!ies unlie PrP -yl"i! <brils. 11 ells inec+e! i+ 22,scr-$ie "r HEJI -*en+s -ls" $r"!uce in+r-cellul-r -rr-ys " c"$-r-ble 25n &iruslie $-r+icles +-+ -re n"+ seen in uninec+e! c"n+r"ls eG+en!in* +ere-li+y " +ese $-r+icles <rs+ !escribe! -ny ye-rs -*" in scr-$ie br-ins. 45

'"re"&er en is"l-+e! inec+i"us $-r+icles -re !isru$+e! +ey rele-senucleic -ci!s -n! $r"+ec+i&e nucleic -ci! bin!in* $r"+eins -n! siul+-ne"uslyl"se 3 l"*s " inec+i&i+y (re&iee! in res. 11 -n! 37). is -!!i+i"n-l e&i!ence$"in+s +" - $r"+ec+e! nucleic -ci! *en"e r-+er +-n +e PrPres +-+ -sn"+ !isru$+e! by +is +re-+en+. i&en suc <n!in*s -n! +e irreu+-blee&i!ence "r u+-ble s+r-ins i+ is re-r-ble +-+ +ere -s been s" li++lesu$$"r+ "r "r in+eres+ in $ursuin* $uri<c-+i"n " nucleic -ci!s r" inec+i"us$-r+icles. #ll " +e -ny inec+i"us $re$-r-+i"ns e -&e +es+e! inclu!in*s+-n!-r! PrPres <brils -!e +" see! +es++ube -yl"i! c"n&ersi"ns17 -&eyiel!e! nucleic -ci!s " R500 n+ ye+ n" -F"r l-b in +e $-s+ 15 y sees+" -&e +es+e! -ny " +eir inec+i"us +issue !eri&e! see! "r c"-c+"r -+eri-lin Au-n+i+ies suBcien+ +" !e+ec+ -n -*en+ nucleic -ci! by +e insensi+i&e *el

s+-inin* e+"!s use!.21 ese -n-lyses -ls" +y$ic-lly eGclu!e "lecules "R200 n+. >"r -&e $re$-r-+i"ns been +es+e! by -ny s$eci<c "lecul-re+"! suc -s PM +" !e+ec+ cy+"$l-sic nucleic -ci!s suc -s re+r"&ir-lseAuences -n! $r"+ec+e! i+"c"n!ri-l I># re*i"ns n"n +" c"$uriy i+inec+i&i+y.21 us +e c""n belie +-+ -*en+s c"n+-in n" nucleic -ci!-$$e-rs +" be b-se! "n +e $ri"n "!el r-+er +-n "n !irec+ eG-in-+i"n " i*ly inec+i"us subcellul-r $re$-r-+i"ns. ec-use nei+er -n inec+i"us "r

























" PrP n"r - c-us-+i&e -*en+s$eci<c nucleic -ci! seAuence -s ye+ been!e<ne! +e n-+ure " +e inec+i"us $-r+icle re-ins unn"n." +":

Nucleic Acids in Infectious Preparations

ere -&e been lii+e! -++e$+s +" !e<ne - nucleic -ci! +-+ is essen+i-l "rinec+i"n. Kne *r"u$ re$"r+e! +-+ s-ll M>#s eG+r-c+e! r" s+-n!-r!263L -s+er PrPres scr-$ie br-in $re$-r-+i"ns -s -ble +" inec+ -ni-lsen !eli&ere! i+ ("r $r"+ec+e! by) recPrP. 68 is resul+ !eser&es "ll"u$!es$i+e +e !isissi&e -$$en!e! c"en+s -b"u+ +is in+eres+in*c"n+ribu+i"n by +" !"in-n+ $ri"n $r"$"nen+s.68 #l+"u* "ur -F"re$-sis -s been +e +r-nsissi"n -n! c-r-c+eri-+i"n " u-n s+r-ins e -&e -ls" l""e! -+ $"+en+i-l -*en+s$eci<c nucleic -ci!sinclu!in* circul-r I>#s +-+ c"$uriy i+ inec+i"us 25 n $-r+icles. erel-+i&e s+-bili+y " -*en+s -n! bi"l"*ic-l $r"$ensi+ies suc -s +u"r"r-+i"n su**es+e! - cy+"$l-sic circul-r I># " 1–4 b21 r-+er +-n -n

M># &irus lie e$-+i+is +-+ is uns+-ble -n! r-$i!ly $r"!uces illi"ns "u+-+e! -n! $en"+y$ic-lly !is+inc+ Au-sis$ecies.Mecen+ -n-lyses " $-r+icle nucleic -ci!s eG+r-c+e! r" inec+i"us cy+"$l-s-&e been -cili+-+e! by +e !e&el"$en+ " ne si$li<e! s+-ble cul+ure"!els r-$i! inec+i&i+y -ss-ys "r i$r"&e! is"l-+i"n " inec+i"us $-r+icles-n! -$$lic-+i"n " -i+ul Pi 29 $"lyer-se -$li<c-+i"ns. 21 e r"bus+ness-n! <!eli+y " +is l-s+ -$$r"-c -s &-li!-+e! bec-use nucle-se $r"+ec+e!ulllen*+ circul-r i+"c"n!ri-l I>#s (+I>#) " 16 b ere re+rie&e! r"inec+i"us cy+"$l-sic r-c+i"ns. '+I># -&e been "un! by PM in e&eryinec+i"us $re$-r-+i"n eG-ine! inclu!in* s+-n!-r! br-in !eri&e! PrPres<brils use! +" see! +es++ube PrP c"n&ersi"ns. =+ is liely +-+ -ll cy+"$l-sic+issue eG+r-c+s use! +" ini+i-+e PrPres ill -ls" s" +I># by PM -s ell

-s r"!en+ re+r"&ir-l seAuences. ile +ese -re unliely +" !e<ne "r enc"!e -*en+ s+r-ins +ey $r"&i!e - *""! $"si+i&e c"n+r"l "r eBcien+ nucleic-ci! eG+r-c+i"n." +":

$ircular &phin8 "NAs4 #nsuspected %8changes with

the *etagenome

Esin* ul+i$le !is$l-ceen+ -$li<c-+i"n ('I#) s+r-+e*ies se&er-l n"&elcircul-r C$inGD I># eleen+s c"$-+ible i+ +e $re!ic+e! &ir-l sie

-&e n" been is"l-+e! r" inec+i"us $-r+icles $r"$-*-+e! in -s+er br-in(i+ 263L scr-$ie) -n! urine 1 cells (i+ HEJI). Enlie +I>#seAuences +-+ ere s$ecies s$eci<c -n! -bun!-n+ +e is"l-+e! $inGseAuences ere $resen+ -+ +e l" le&els eG$ec+e! "r - -*en+ in sucr"se*r-!ien+ $uri<e! $-r+icles. ey ere ""l"*"us by PM re*-r!less "s$ecies "r -*en+ s+r-in. ese +" I>#s ere n"+ !e+ec+-ble in -ny " +eenyes ceic-ls "r s"lu+i"ns use! &eriyin* +eir "ri*in in +e $-r+icle$re$-r-+i"ns. ec-use +e KMHs in +ese +" $inG eleen+s ere -ls"$resen+ by PM -lbei+ -+ - uc l"er le&el in uninec+e! $-r-llel















$re$-r-+i"ns +eir r"le in inec+i"n is in!e+erin-+e. @"e&er +eir r"lec-n be e&-lu-+e! usin* -n+isense s+r-+e*ies. =+ -y -ls" be in"r-+i&e +"eG-ine $"+en+i-l u+-+i"ns in +e uninec+e! ""l"*s. =n inec+i"us$-r+icle $re$-r-+i"ns - e -!!i+i"n-l $r"+ec+e! circul-r I>#s -&e -ls" beeni!en+i<e! -n! +ese !eser&e ur+er s+u!y *i&en +e in!e$en!en+ s+r-inre$lic-+i"n !yn-ics -n! en&ir"nen+-l "ri*in " s. ese +y$es "

seAuences -l+ern-+i&ely c"ul! be in&"l&e! in +e recrui+en+ " n"ninec+i"us-yl"i!s n"+ "nly in s bu+ in "+er neur"!e*ener-+i&e !ise-ses.Me-r-bly b"+ +e circul-r 1.8 b -n! - 2.4 b $inG eleen+s c"n+-in"$en re-!in* r-e (KMH) ""l"*ies i+ $"r+i"ns " +e l-r*e circul-r 12b $l-si!s " #cine+"b-c+er bu+ +e $-ren+ b-c+eriu -s n"+ -$$-ren+ in+e inec+i"us eG+r-c+s. ese +" $inG eleen+s -ls" c"n+-in n"nc"!in*in+er&enin* seAuences +-+ -re n"+ in +e !-+-b-se i$lic-+in* -ne&"lu+i"n-ry !ierence r" +e s+-n!-r! b-c+eri-l $l-si!s. #cine+"b-c+er-re i!es$re-! in +e en&ir"nen+ inclu!in* s"il -n! -+er -re -n+ibi"+icresis+-n+ -n! -re c"ens-l inec+i"ns +-+ -re n"+ +y$ic-lly $-+"*enic.

us +ey r-ise +" un!-en+-lly ne c"nce$+s. Hirs+ +-+ l" $-+"*enici+yen&ir"nen+-l I>#s -y resi!e in - Auiescen+ "r l-+en+ "r in --ls

un+il +e "r*-nis is s+resse!. ec"n! $inG eleen+s -y re$resen+ +e+i$ " +e iceber* " uneG$ec+e! e+-*en"ic eGc-n*es i+ --ls: -r-+er eGci+in* ne !irec+i"n i+ br"-! r-i<c-+i"ns." +":

&ummary

e s+ruc+ure -n! s+r-in!e+erinin* "lecul-r c"$"nen+s " inec+i"us $-r+icles re-ins unn"n. #n en"r"us &-rie+y " e&i!ence c"n+r-!ic+s +ec"nclusi"n +-+ inec+i"us -*en+s -re -!e " "s+ PrP i+"u+ nucleic-ci! "r -n en&ir"nen+-l c"$"nen+. Hirs+ !ieren+ -*en+ s+r-ins *i&e +e

s-e PrPres $-++ern -n! c"n&ersely s-$les i+ &ery !ieren+ PrPres$-++erns c-n $r"$-*-+e +e i!en+ic-l inec+i"us -*en+. us "bser&e! PrPc"n"rers !" n"+ enc"!e "r $re!ic+ s+r-ins. ec"n! -ll "rs " !e+ec+-blePrP c-n be !es+r"ye! i+ n" l"ss " inec+i&i+y. PrP -s -ls" beenun!e+ec+-ble in cells i+ i* inec+i"us +i+ers. ir! +e "s+ rec"*nies-n! "un+s e-rly inn-+e iune !eenses -*-ins+ in!i&i!u-l -*en+s -n!+is !e+erines l-+ency -n! incub-+i"n +ie. H"ur+ PrPres -yl"i! -$$e-rs-s $-r+ " - l-+e !eense ec-nis -*-ins+ - "rei*n -*en+ -n! -*en+re$lic-+i"n !e"ns+r-+es - &-s+ly !ieren+ +r-Fec+"ry +-n +e c"n&ersi"nine+ics " PrPres (+e Cinec+i"usD "r). Hi+ PrP -c+s -s - reAuire! "s+rece$+"r "r -*en+ sur&i&-l. =n +is c-$-ci+y i+ c-n $r"+ec+ +e -*en+ ile-ll"in* +e "s+ +" sur&i&e "r ye-rs. iG+ -s "+er P= $r"+eins PrP

-cili+-+es cell+"cell +r-nser -n! c-n be use! by se&er-l inec+i"us -*en+sn"+ Fus+ s. e&en+ -s in inec+i"ns "+er &iruses c-n in!uceis"l!e! $r"+ein C$ri"nD -**re*-+es -s $-r+ " -n -n+i&ir-l inn-+e iuneres$"nse. i*+ +e -bili+y +" "l! in+" -n -yl"i! s+-+e is - $r"$er+y s-re!by -ny $r"+eins -n! $e$+i!es.#yl"i! -**re*-+i"n is - $r"cess +-+ is i*ly c"nser&e! in e&"lu+i"n -n! i+!"es n"+ reAuire inec+i"n. =n ye-s+ suc c"n&ersi"ns -re in&"l&e! in - i!er-n*e " unc+i"ns inclu!in* +r-nscri$+i"n-l -n! +r-nsl-+i"n-l re*ul-+i"n.38







Iense resis+-n+ b-c+eri-l bi"<ls unc+i"n in s"ci-li-+i"n -n! $r"+ec+i"n 69 -n! c-n be c"nsi!ere! +"*e+er i+ --li-n -yl"i!s inclu!in* PrP -n!#I $l-Aues +-+ c"n+-in -ny "+er eleen+s.23 =nec+i"n $"ses -!!i+i"n-luneG$l"re! "$$"r+uni+ies. e !isc"&ery " b-c+eri-l $l-si!lie eleen+s-ss"ci-+e! i+ inec+i"us $-r+icles r-ises +e issue " unsus$ec+e!eGc-n*es be+een --ls -n! b-c+eri-l &ir-l eleen+s in !ise-se. "e

" +ese &ir-l eleen+s -y be +e r""+ c-use " s -s ell -s - !i&ersi+y " cr"nic c"n!i+i"ns. #l+ern-+i&ely suc eleen+s -y $r""+e +e-**re*-+i"n " <brill-r $r"+eins in neur"!e*ener-+i"ns " unn"n e+i"l"*y.'e+-*en"ic eleen+s -l"n* i+ en&ir"nen+-l +"Gins surely !eser&ebr"-!er -++en+i"n -s c-us-l -c+"rs in #I -n! "+er l-+e"nse+ !ise-ses." +":

Acknowledgments

is "r -s su$$"r+e! by >=@ *r-n+ >=>I *r-n+ M01 012674" +":

"isclosure of Potential $onflicts of Interest

>" $"+en+i-l c"nic+s " in+eres+ ere !iscl"se!." +":

3ootnotes

Pre&i"usly $ublise! "nline:.l-n!esbi"science.c"%F"urn-ls%&irulence%-r+icle%24838

" +":

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http://www.landesbioscience.com/journals/virulence/article/24838/



http://dx.doi.org/10.1126%2Fscience.279.5352.827












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-n in&-si&e rece$+"r. J =un"l. 2012;189:1540–4. !"i:10.4049%Fiun"l.1103332. YPub'e!Z Yr"ss Me Z62. @"u H un , èn* @ -u* Ji-n* \^ en `J. '#V "rs unc+i"n-l$ri"nlie -**re*-+es +" -c+i&-+e -n! $r"$-*-+e -n+i&ir-l inn-+e iuneres$"nse. ell. 2011;146:448–61. !"i: 10.1016%F.cell.2011.06.041. YP' ree-r+icleZ YPub'e!Z Yr"ss Me Z63. We J '-ni-+is . # $ri"nlie +ri**er " -n+i&ir-l si*n-lin*. ell.2011;146:348–50. !"i: 10.1016%F.cell.2011.07.018. YPub'e!Z Yr"ss Me Z64. Ier-+c =, ,ieb-n . Pri"n$ri"n in+er-c+i"ns. Pri"n. 2007;1:161–9.!"i: 10.4161%$ri.1.3.4837. YP' ree -r+icleZ YPub'e!Z Yr"ss Me Z65. '--r-&- > L"&-cs "c-r"&- K -&+cen" M #leGee&- = u!-@ e+ -l. Mec"bin-n+ $ri"n $r"+ein in!uces - ne +r-nsissible $ri"n !ise-se

in il!+y$e -ni-ls. #c+- >eur"$-+"l. 2010;119:177–87. !"i:10.1007%s004010090633G. YP' ree -r+icleZ YPub'e!Z Yr"ss Me Z66. '-nueli!is , 'ur!"c '-nueli!is . P"+en+i-l in&"l&een+ "re+r"&ir-l eleen+s in u-n !een+i-s. ib- H"un! y$. 1988;135:117–34. YPub'e!Z67. -ncell"++i '--l P "er&ille M Ii-c # r"n I Picc-r!" P e+ -l.P"s++r-nsl-+i"n-l c-n*es +" PrP -l+er +r-nsissible s$"n*i"rence$-l"$-+y s+r-in $r"$er+ies. 'K J. 2013;32:756–69. !"i:10.1038%eb"F.2013.6. YP' ree -r+icleZ YPub'e!Z Yr"ss Me Z68. i"ne-u Muc"uG ' Vi*nier > ,eb"n P Hreire ""y e+ -l.-ll cri+ic-l M>#s in +e scr-$ie -*en+.++$:%%!l.-n!le.ne+%10101%n$re.2009.3344.1 >-+ Prece!in*s. 2009:3344.69. P-+- I ei ^ ucu&-l-s # @-+ I@ erl" I, -ll I. ell c"n+-c+!e$en!en+ "u+er ebr-ne eGc-n*e in yG"b-c+eri-: *ene+ic !e+erin-n+s-n! ec-nis. P," ene+. 2012;8:e1002626. !"i:10.1371%F"urn-l.$*en.1002626. YP' ree -r+icleZ YPub'e!Z Yr"ss Me Z70. '-nueli!is Li J #n*el" J> '-nueli!is ,. eri-l $r"$-*-+i"n "reu+el!+J-"b !ise-se in *uine- $i*s. Pr"c >-+l #c-! ci E #.1976;73:223–7. !"i: 10.1073%$n-s.73.1.223. YP' ree -r+icleZ YPub'e!Z Yr"ss Me Z71. '-nueli!is "r*-c J '-nueli!is ,. =n+ers$ecies +r-nsissi"n "reu+el!+J-"b !ise-se +" yri-n -s+ers i+ reerence +" clinic-lsyn!r"es -n! s+r-ins " -*en+. Pr"c >-+l #c-! ci E #. 1978;75:3432–6.!"i: 10.1073%$n-s.75.7.3432. YP' ree -r+icleZ YPub'e!Z Yr"ss Me Z

Jurnal OPri"n. 2012 #$ril 1; 6(2): 108–115.!"i: 10.4161%$ri.18666P'=I: P'3366352'"lecul-r $-+"*enesis " s$"r-!ic $ri"n !ise-ses in -n

Jiri . --rd#u+"r in"r-+i"n / "$yri*+ -n! ,icense in"r-+i"n /


http://dx.doi.org/10.1016%2Fj.virol.2008.12.005


http://dx.doi.org/10.4049%2Fjimmunol.1103332




http://dx.doi.org/10.1016%2Fj.cell.2011.06.041





http://dx.doi.org/10.4161%2Fpri.1.3.4837







http://dx.doi.org/10.1038%2Femboj.2013.6

http://hdl.handle.net/10101/npre.2009.3344.1



http://dx.doi.org/10.1371%2Fjournal.pgen.1002626








http://dx.doi.org/10.1016%2Fj.virol.2008.12.005


http://dx.doi.org/10.4049%2Fjimmunol.1103332
















http://dx.doi.org/10.1038%2Femboj.2013.6

http://hdl.handle.net/10101/npre.2009.3344.1



http://dx.doi.org/10.1371%2Fjournal.pgen.1002626











-ble +ubn-il -ble 1. +i"l"*ic cl-ssi<c-+i"n " u-n $ri"n !ise-ses" +":Hr" sl" &irus +" +e $ri"n c"nce$+

$"r-!ic reu+el!+J-"b !ise-se (sJI) is +e "s+ c""n "r " u-n

s$"n*i"r ence$-l"$-+y -cc"un+in* "r 85Q " -ll u-n $ri"n!ise-se.8 e +er Creu+el!+J-"b !ise-seD (JI) -s in+r"!uce! by#l"ns '-ri- J-"b in 1921 " reerre! +" - $re&i"us c-se !escribe! by@-ns er-r! reu+el!+ in 1920.910 ese "ri*in-l c-ses ere clinic-llye+er"*ene"us -n! neur"$-+"l"*ic re&ie " +e is+"ric-l -+eri-l i+"!ern +""ls $r"&i!e! c"n<r-+i"n " +e !i-*n"sis " JI in "nly +" " +e"ri*in-l <&e c-ses.11 K&er +e neG+ +" !ec-!es +e clinic"$-+"l"*ic-lcl-ssi<c-+i"n " JI re-ine! uncer+-in -n! "r eG-$le ils"n c"nclu!e!+-+ JI is - C!u$in* *r"un! "r se&er-l r-re c-ses " $resenile!een+i-D12. #l+"u* "n"*r-$ by Lirscb-u13 lis+e! +e clinic-l -n!$-+"l"*ic c-r-c+eris+ics " 150 c-ses !i-*n"se! be"re 1965 i+ inclu!e!-ls" c-ses suc -s reu+el!+Os "ri*in-l c-se ic "ul! n"+ ul<ll cri+eri-

"r +e !i-*n"sis " JI +"!-y. =$"r+-n+ly in +e 1960s >e&in -n! J"nes!escribe! +e +y$ic-l clinic-l sy$+"s elec+r"ence$-l"*r- () -n!neur"$-+"l"*ic c-n*es inclu!in* s$"n*i"r c-n*e ic +"*e+er -ren" rec"*nie! -s +e $-r-!i* e-+ures " s$"r-!ic JI.14 ubseAuen+lyne s$"r-!ic "rs " +e s$"n*i"r ence$-l"$-+ies i+ uniAue$en"+y$ic e-+ures ere !escribe!; s$eci<c-lly s$"r-!ic -+-l ins"ni- (H=)in 19971516 -n! +e l-+es+ liely ne c-n!i!-+e &-ri-ble $r"+e-sesensi+i&e$ri"n"$-+y (VPPr) in 2008.17

"n+r"&ersy c"ncernin* +e c-use " u-n s$"n*i"r ence$-l"$-+ies-s $"l-rie! +e scien+i<c c"uni+y "r !ec-!es. e 1950s s-c"nsi!er-ble in+eres+ in -n e$i!eic " - neur"!e*ener-+i&e !ise-se uruc-r-c+erie! $rinci$-lly by - $r"*ressi&e cerebell-r -+-Gi- -"n* +e H"re$e"$le " +e -s+ern @i*l-n!s " P-$u- >e uine-.1819 Hiel!"r by-rle+"n -F!use -n! Vincen+ ì*-s su**es+e! +-+ uru -s +r-nsi++e!!urin* c-nnib-lis+ic e-s+s.20 =$"r+-n+ly in 1959 @-!l" $"in+e! "u+ +esiil-ri+ies be+een uru -n! scr-$ie " see$ -+ +e neur"$-+"l"*ic -n!clinic-l le&els -n! su**es+e! +-+ u-n !ise-ses i*+ -ls" be+r-nsissible.21 ubseAuen+ +r-nsissi"n " uru (in 1966) -n! +en JI (in1968) by in+r-cerebr-l in"cul-+i"n " br-in ""*en-+es in+" ci$-nees"r ic -s c"n!uc+e! by -F!use ibbs -n! c"lle-*ues -s -l-n!-r !isc"&ery ic le! +" +e c"nce$+ " +e C+r-nsissible s$"n*i"rence$-l"$-+iesD2223. e +r-nsissi"n " ers+-nn+r]usslerceiner!ise-se () "ll"e! in 198124 -n! -+-l -ili-l ins"ni- (HH=) in 1995.25=n+eres+in*ly J-"b sus$ec+in* in is "ri*in-l "bser&-+i"ns +-+ +e c"n!i+i"ni*+ be +r-nsissible in"cul-+e! r-bbi+s eG$erien+-lly in -n -++e$+ +"!e"ns+r-+e +is in +e 1920s.26 @"e&er +-ns +" +e i$"r+-n+ r"le "seren!i$i+y in science is eG$erien+ -s unsuccessul -n! e n" n"+-+ r-bbi+s -re uniAuely resis+-n+ +" $ri"n inec+i"ns.27

e +r-nsissi"n " JI -n! " uru -ll"e! re<neen+ " +e !i-*n"s+ic$-+"l"*ic cri+eri- "r u-n s$"n*i"r ence$-l"$-+y -n! le! +" +e



c"nclusi"n +-+ -ll +e u-n c"n!i+i"ns s-re c""n is+"$-+"l"*ice-+ures: s$"n*i"r &-cu"l-+i"n (-ec+in* -ny $-r+ " +e cerebr-l *r-y-++er) neur"n-l l"ss -n! -s+r"cy+ic $r"lier-+i"n +-+ -y be -cc"$-nie!by -yl"i! $l-Aues.2831 Kn -n-l"*y i+ scr-$ie in see$ i+ -s -ssue!+-+ +e c-us-+i&e -*en+ us+ be s"e +y$e " -+y$ic-l Csl" &irusD +e +eri*ur!ss"n c"ine! in 1954 "r scr-$ie inec+i"n.232 Me*re++-bly !es$i+e

eG+ensi&e e"r+s in ur"$e -n! +e E n" n"n"s+ I># "r M># c"ul! be"un! -n! - *r"in* b"!y " !-+- $"in+e! +" - c-us-+i&e -*en+ -&in*uniAue c-r-c+eris+ics.3334 '"s+ rese-rcers +"!-y -cce$+ +e "!el-cc"r!in* +" ic +e inec+i"us $-+"*en res$"nsible "r u-n $ri"n!ise-ses is -n -bn"r-l $r"+ein !esi*n-+e! PrPc 1.

e !isc"&ery +-+ $r"+eins c"ul! be inec+i"us re$resen+e! - ne $-r-!i*" "lecul-r bi"l"*y -n! e!icine. #l+"u* "ri*in-lly !eee! ere+ic-l +is$r"+ein"nly "!el is n" su$$"r+e! by - e-l+ " bi"ceic-l *ene+ic -n!-ni-l s+u!ies.63538 '"re"&er +e c"nce$+ " $ri"n !ise-ses -si$"r+-n+ i$lic-+i"ns "r "+er neur"!e*ener-+i&e !is"r!ers. Mecen+ s+u!iesi+ #yl"i! +-u asynuclein un+in*+in -n! su$er"Gi!e !isu+-se 1

su**es+ +-+ "lecul-r -n! cellul-r ec-nis +-+ ere <rs+ !isc"&ere! ins+u!ies " $ri"ns -re in&"l&e! in +e $-+"*enesis " "+er neur"!e*ener-+i&e!is"r!ers -ss"ci-+e! i+ +e -ccuul-+i"n " is"l!e! $r"+eins inclu!in*P-rins"nis @un+in*+"n !ise-se -y"+r"$ic l-+er-l scler"sis (#,) -n!#leier !ise-se.3943" +":P-+"*ene+ic ec-niss " u-n s$"r-!ic $ri"n !ise-ses

e b-sic e&en+ s-re! by -ll +ree "rs " $ri"n !ise-ses – s$"r-!icineri+e! -n! -cAuire! by inec+i"n – is - c-n*e in c"n"r-+i"n " +en"r-l "r cellul-r PrP (PrP) ic is c"n&er+e! in+" - $-+"*enic PrP is""rc""nly i!en+i<e! -s PrPc "r $r"+"+y$ic scr-$ie (c) PrP.1 @u-n PrP isenc"!e! by +e PrP *ene (PM>P) "n cr""s"e 20 -n! eG$resse! -+!ieren+ le&els in "s+ --li-n cells. =+ c"$rises 209 -in" -ci!s (23–231) +" si+es " >line! *lyc"syl-+i"n - !isul<!e b"n! -n! - *lyc"li$i!-nc"r.4449 e &-ri-ble !e*ree " *lyc"syl-+i"n is res$"nsible "r +e$resence " !i "n" -n! un*lyc"syl-+e! "rs " PrP. ec-use " +e*lyc"li$i! -nc"r "s+ " +e PrP is eG+r-cellul-rly line! in s$eci-lie!c"les+er"lric !"-ins (c-&e"li) " +e cell $l-s- ebr-ne.4850 =nn"r-l c"n"r-+i"n u-n PrP c"$rises - +erin-l *l"bul-r !"-in(in&"l&in* resi!ues 127–231) ic c"nsis+s " +ree aelices -n! +" s"r+see+s.51 =n c"n+r-s+ +e >+erinus is uns+ruc+ure!.51

e PrPc in c"n+r-s+ is $-+"*enic inec+i"us -n! !is$l-ys !ieren+bi"$ysic-l e-+ures "rin* ins"luble -**re*-+es " !ieren+ sies i+$re!"in-n+ly see+ sec"n!-ry s+ruc+ure; +e +erin-l re*i"n is rel-+i&elyresis+-n+ +" $r"+e"ly+ic !e*r-!-+i"n.5254 e c"n"r-+i"n-l +r-nsi+i"n +-+un!erlies +ese $r"n"unce! c-n*es is belie&e! +" in&"l&e re"l!in* " +e +erin-l re*i"n ereby +e aelic-l s+ruc+ures " PrP -re re$l-ce! by see+ +" !ieren+ eG+en+s -n! i+ &-ri-ble $-++erns.55 #l+"u* ins"lubili+y-n! $r"+e-se resis+-nce ere +e "ri*in-l !e<nin* e-+ures " PrPc +e



<n!in* " $r"+e-sesensi+i&e s-ll "li*"ers " $-+"*enic PrPc 56 57si*ni<c-n+ly br"-!ene! +e s$ec+ru " $-+"*enic c"n"rers.

#l+"u* s"e -u+"rs belie&e +-+ +e +"Gici+y in $ri"n !ise-se c-n beeG$l-ine! -s - l"ss " unc+i"n " PrP !ue +" +e c"n"r-+i"n-l+r-ns"r-+i"n58 "+ers -r*ue +-+ - *-in " +"Gic unc+i"n is "re

liely.5960 >e&er+eless +ere is *ener-l -*reeen+ +-+ PrP ser&es -s -subs+r-+e "r c"n&ersi"n +" PrPc -n! -s - -F"r rece$+"r "r +"Gic eec+s "PrPc. us +e neur"$r"+ec+i&e unc+i"n $ysi"l"*ic-lly $r"&i!e! by PrPc"ul! be l"s+ "ll"in* i+s c"n&ersi"n +" PrPc. e $re&-ilin* $resence "PrPc "n neur"n-l $l-s- ebr-ne -ls" -+ +e syn-$se i*+ eG$l-in +ei!es$re-! s$"n*i"r !e*ener-+i"n ic c-n be &iee! -s in+r-cellul-re!e-. #ll +ese c-n*es -re $-+"*n""nic " sJI. #$"$+"sis -n!"Gi!-+i&e s+ress -re re$"r+e! +" "ccur en PrPc -**re*-+es "r -+ +e cellsur-ce -n! -y ell c"n+ribu+e +" +e neur"n-l cell l"ss +-+ is $r"inen+ in$ri"n !ise-ses " l"n* !ur-+i"n -n! in $ri"n !ise-ses lie H= ic -nies+n" "r ini-l s$"n*i"sis -s ell -s se&ere neur"n-l l"ss.61 #s+r"*li"sis -c""n re-c+i"n +" inFury is c"nsi!ere! - sec"n!-ry res$"nse.

" +": e "ri*in -n! $en"+y$ic e+er"*enei+y " sJI

e&er-l eG$l-n-+i"ns -&e been $r"$"se! "r +e e+i"l"*y " s$"r-!ic $ri"n!ise-ses. ese inclu!e s$"n+-ne"us s"-+ic u+-+i"ns in +e PM>P *ene "rr-re s+"c-s+ic c"n"r-+i"n-l c-n*es in +e s+ruc+ure " PrP 62. eseeG$l-n-+i"ns $resu$$"se +-+ +e u+-n+ PrPc "ul! -&e +" be c-$-ble "recrui+in* il!+y$e PrP; "e&er +is $r"cess ic i*+ "ccur i+ s"eu+-+i"ns "r c"n"r-+i"ns bu+ is unliely i+ "+ers.63 #cc"r!in* +" -sec"n! eG$l-n-+i"n l" -"un+s " PrPclie is""rs -re n"r-lly $resen+in br-in -n! $"ssibly b"un! +" "+er $r"+eins suc -s e-+ s"c $r"+eins"e&er +is $r"+ec+i&e ec-nis -ils i+ -*in*.6465 Hin-lly i+ -s beensu**es+e! +-+ -+ le-s+ s"e c-ses " -$$-ren+ sJI resul+ r" c"&er+ l"le&el eG$"sure +" - Cc""n eG+ern-l -c+"rD66.

i+ "re c-ses in&es+i*-+e! -+er +e "ri*in-l re$"r+s by J-"b i+ bec-ecle-r +-+ +e clinic-l -s ell -s is+"$-+"l"*ic e-+ures " sJI -rere-r-bly !i&erse $er-$s -in* +e u-n $ri"n !ise-ses +e "s+e+er"*ene"us " -ll neur"!e*ener-+i&e !ise-se. Kn +e b-sis " $re!"in-n+clinic-l -n! $-+"l"*ic e-+ures +e "ll"in* $en"+y$ic sub+y$es " sJIere $r"$"se! in +e 1980s: 1) y"cl"nic "r c"r+ic"s+ri-+-ls$in-l 2)--ur"+ic "r @ei!en-in 3) cl-ssic-l "r !iuse 4) +-l-ic 5) -+-Gic "rcerebell-r -n! 6) -y"+r"$ic.6769 Mese-rcers +"!-y *ener-lly -*ree +-++e *en"+y$e -+ c"!"n 129 " +e cr""s"-l *ene PM>P -n! +" s"e!e*ree +e $en"+y$es " +ese !ise-ses un!erlie susce$+ibili+y +" $ri"n!ise-ses.5 #!!i+i"n-lly -ny lines " e&i!ence r" eG$erien+s i+l-b"r-+"ry $ri"n s+r-ins su$$"r+ +e &ie +-+ +e $en"+y$e " sJI?i+s!is+inc+i&e incub-+i"n +ie clinic-l e-+ures -n! br-in $-+"l"*y?isenci$ere! in +e s+r-ins$eci<c c"n"r-+i"n " PrPc 5670–73. @"e&er inc"n+r-s+ +" +e eG$erien+s i+ l-b"r-+"ry r"!en+ $ri"n s+r-ins in ic +e!i*es+i"n " br-in PrPc i+ $r"+e"ly+ic enye $r"+ein-se L (PL)c"nsis+en+ly resul+s in - sin*le $r"+e-seresis+-n+ !"-in i+ -ss 19 I-



+e "u+c"e in sJI is "re c"$leG. Iis+inc+i&e *lyc"syl-+i"n $-++erns -n!u$ +" "ur PLresis+-n+ r-*en+s " +e $-+"*enic $ri"n $r"+ein (rPrPc)"un! in sJI br-ins -re e-sily !is+in*uis-ble "n es+ern bl"+ ().5717477

e <n!in*s +"*e+er i+ u-n PM>P *ene $"ly"r$is le! P-rci

-be++i -n! c"lle-*ues +" $"si+ - clinic"$-+"l"*ic-l cl-ssi<c-+i"n " sJIin+" <&e "r siG sub+y$es; n"+-bly +e c-r-c+eris+ics " PrPc bree! +rueu$"n +r-nsissi"n +" susce$+ible +r-ns*enic ice -n! uine- $i*s (-&i-$"rcellus).5717478 #n -l+ern-+i&e cl-ssi<c-+i"n " +e PrPc +y$es -n! +eir$-irin* i+ JI $en"+y$es -s been $r"$"se! by "llin*e -n!c"ll-b"r-+"rs.37757679 is cl-ssi<c-+i"n !iers r" +e $re&i"us "ne in+" -F"r -s$ec+s: <rs+ i+ rec"*nies +ree (n"+ +") PrPc elec+r"$"re+ic"bili+ies -n! sec"n! i+ -ls" i!en+i<es PrPc is""rs i+ !ieren+ r-+i"s "+e +ree PrP *lyc""rs.37 #l+"u* +e !ise-se $en"+y$es " $-+ien+s i+sJI -re re-r-bly e+er"*ene"us 21 I- r-*en+s " un*lyc"syl-+e!PrPc (y$e 1) reAuen+ly !ier r" +e !ise-se !ur-+i"n -n! $en"+y$es-ss"ci-+e! i+ +e 19 I- r-*en+s " un*lyc"syl-+e! PrPc (y$e

2).357174

uul-+i&ely +ese <n!in*s -r*ue +-+ +e PrPc +y$e re$resen+s ye+ -n-!!i+i"n-l -F"r "!i<er " +e $en"+y$e in u-n $ri"n !ise-ses;-cc"r!in*ly b-se! clinic"$-+"l"*ic cl-ssi<c-+i"ns bec-e -n i$"r+-n++""l in s+u!ies " $ri"n $-+"*enesis in u-n br-ins -n! in +r-ns*enic ice"!els.3771 ec-use +" !is+inc+ PL cle-&-*e si+es in PrPc y$es 1 -n! 2"s+ liely s+e r" !is+inc+ c"n"r-+i"ns s"e in&es+i*-+"rs c"n+en!+-+ PrPc y$es 1 -n! 2 c"!e !is+inc+ $ri"n s+r-ins.3717580 @"e&er +ee+er"*enei+y " sJI -l"n* i+ - *r"in* nuber " s+u!ies inclu!in*bi"-ss-ys -ll su**es+ +-+ +e r-n*e " $ri"ns c-usin* sJI eGcee!s +enuber " c-+e*"ries rec"*nie! i+in +e curren+ b-se!clinic"$-+"l"*ic scees.8183 #!!i+i"n-lly recen+ <n!in*s " +e c""ccurrence " PrPc y$es 1 -n! 2 in 40Q "r "re sJI c-ses cre-+e! -c"nun!ru -n! su**es+e! +-+ +e "ri*in-lly "bser&e! !ierences ereAu-n+i+-+i&e r-+er +-n Au-li+-+i&e.8489 Hin-lly u$ +" 90Q " br-in PrPc insJI elu!es -n-lysis bec-use i+ is !es+r"ye! by $r"+ein-seL +re-+en+ic is necess-ry +" eliin-+e PrP 81. "nseAuen+ly +e c"n"r-+i"n "rr"le " +is -F"r $r"+e-sesensi+i&e (s) r-c+i"n " PrPc in +e $-+"*enesis" +e !ise-se is - subFec+ " s$ecul-+i"n.648190 us n" !irec+ s+ruc+ur-l!-+- -re -&-il-ble "r sJI br-in PrPc bey"n! +e e&i!ence +-+ i+ isresis+-n+ +" $r"+e"ly+ic !i*es+i"n. >e&er+eless +" !e+erine +e ulls$ec+ru " sJI $ri"n s+r-ins -n! +e c"n"r-+i"n-l e-+ures in +e$-+"*enic u-n $ri"n $r"+ein *"&ernin* re$lic-+i"n " sJI $ri"ns isun!-en+-l "r +e r-+i"n-l !e&el"$en+ " !i-*n"s+ic -s ell -s +er-$eu+ics+r-+e*ies." +":>"&el c"n"r-+i"n-l e+"!s !eri&e! r" - c"n"r-+i"n!e$en!en+iun"-ss-y (I=)

ree "bs+-cles -&e sl"e! $r"*ress in +e rese-rc " u-n $ri"ns:$en"+y$ic &-ri-bili+y " sJI "n c"$leG *ene+ic b-c*r"un! bi"s-e+y



c"ns+r-in+s -n! l-c " sui+-ble +""ls "r s+u!yin* "lecul-r c-r-c+eris+icsbey"n! +y$in*. #iin* +" -!&-nce "ur un!ers+-n!in* " +e "lecul-r$-+"*enesis " u-n $ri"n !ise-ses e !e&el"$e! +e c"n"r-+i"n!e$en!en+ iun"-ss-y (I=)568191 +" !e+erine +e c"n"r-+i"n-lr-n*e -n! s+r-in!e$en!en+ "lecul-r e-+ures " sJI PrPc <rs+ in $-+ien+s" ere ""y*"us "r c"!"n 129 " +e PM>P *ene.92 &en rel-+i&ely

inu+e &-ri-+i"ns in - s"luble $r"+ein s+ruc+ure c-n be !e+erine! bye-surin* c"n"r-+i"n-l s+-bili+y in - !en-+ur-n+ suc -s !n @l.93E+iliin* +is c"nce$+ e !esi*ne! - $r"ce!ure in ic PrPc is <rs+eG$"se! +" !en-+ur-n+ !n @l -n! +en eG$"se! +" eur"$iul-bele! #b-*-ins+ +e e$i+"$es i!!en in +e n-+i&e c"n"r-+i"n.56 #s +ec"ncen+r-+i"n " !n @l incre-ses PrPc !iss"ci-+es -n! un"l!s r"n-+i&e see+s+ruc+ure! -**re*-+es -n! "re e$i+"$es bec"e -&-il-ble+" -n+ib"!y bin!in*. ese eG$erien+s in&"l&e ins"luble "li*"eric "rs "PrPc -n! !en-+ur-+i"n " +is $r"+ein is irre&ersible in &i+r"; c"nseAuen+ly+e ibbs ree ener*y c-n*e () " PrPc c-nn"+ be c-lcul-+e!.94

ere"re e c"se ins+e-! +" use +e !n @l &-lue "un! -+ +e -l-Gi-l !en-+ur-+i"n (Y!n@lZ1%2) -s - e-sure " +e rel-+i&e

c"n"r-+i"n-l s+-bili+y " PrPc. e !ierences in s+-bili+y re&e-l e&i!ence" !is+inc+ c"n"r-+i"ns " PrPc 56 93 94.

" e-sure +e c"ncen+r-+i"n " !ieren+ "rs " PrPc -n! "ll" +eun"l!in* e use! eur"$iul-bele! #b 3H495 (e$i+"$e resi!ues 107–112)"r !e+ec+i"n -n! 8@4 #b (e$i+"$e resi!ues 175–185)96 +" c-$+ure u-nPrPc in - s-n!ic I= "r-+.8197 e -n-ly+ic-l sensi+i&i+y -n! s$eci<ci+y" +e "$+iie! I= "r !e+ec+i"n " PrPc -s $re&i"usly re$"r+e! by us -n!"+ers in nuer"us $ublic-+i"ns56819198100 -n! -s been s"n +" be-s l" -s 500 * (20 -++""les) " PrPc ic is siil-r +" +e sensi+i&i+y" u-n $ri"n bi"-ss-y in *('@u2')5378%Prn$0%0 ice.81 ec-use I= isn"+ !e$en!en+ "n $r"+e-se +re-+en+ i+ -ll"e! us +" -!!ress un!-en+-lAues+i"ns c"ncernin* +e c"ncen+r-+i"n -n! c"n"r-+i"n " !ieren+is""rs " sJI PrPc inclu!in* $r"+e-sesensi+i&e (s) -n! $r"+e-seresis+-n+(r)PrPc 92.

e !iss"ci-+i"n -n! un"l!in* " PrPc in +e $resence " incre-sin*c"ncen+r-+i"n " !n @l c-n be !escribe! -s "ll"s:

YPrPcZn f YsPrPcZn f iPrP f uPrP

ere YPrPcZn -re n-+i&e -**re*-+es " PrPc YsPrPcZn -re s"luble$r"+e-sesensi+i&e "li*"ers " PrPc iPrP is -n in+ere!i-+e -n! uPrP isc"$le+ely un"l!e! (!en-+ure!) PrP.535794 e I= "ni+"rs +e *l"b-l+r-nsi+i"n r" n-+i&e -**re*-+es +" ully !en-+ure! "n"ers " PrPc. =nc"n+r-s+ +e b-se! +ecniAues "ni+"r ei+er +e $-r+i-l s"lubili-+i"n "PrPc 101 "r c"n&ersi"n " rPrPc +" $r"+e-sesensi+i&e c"n"rers72 -+ereG$"sure +" !en-+ur-n+. #s - resul+ +e s+-bili+y !-+- "n s"luble $r"+e-sesensi+i&e "li*"ers -n! in+ere!i-+es " PrPc c-nn"+ be "b+-ine! i+ +ecniAues -n! -y eG$l-in s"e -re!ly !ieren+ &-lues.102" +":+ruc+ur-l e+er"*enei+y " sJI PrPc -n! +e r"le " sPrPc in $-+"*enesis



Kur recen+ <n!in* " 6"l! !ierence in c"ncen+r-+i"ns " PrPc be+een y$e 1 -n! y$e 2 PrPc(129') in +e r"n+-l c"r+eG -s sur$risin* e&en+"u* s"e &-ri-bili+y -s +" be eG$ec+e! !ue +" !ierences in +e$re!"in-n+ly -ec+e! -re-s in !is+inc+ sJI $en"+y$es.8192 '"re"&er+e -&er-*e le&els " PrPc ere u$ +" 100"l! l"er +-n +"se in s+-n!-r!

l-b"r-+"ry $ri"n "!els suc -s yri-n -s+ers inec+e! i+ c237$ri"ns56; -n! +"*e+er i+ +e u$ +" 100"l! &-ri-bili+y i+in e-c$en"+y$ic *r"u$ +ese l"er le&els " PrPc -y eG$l-in y s"e sJIc-ses -re !iBcul+ +" +r-nsi+ -n! y l"er en!$"in+ +i+ers -re "b+-ine!i+ u-n $ri"ns in +r-ns*enic ice eG$ressin* u-n "r cieric PrP 3771 81 103.

E$ +" 90Q " +e $-+"*enic $ri"n $r"+ein in sJI is $r"+e-sesensi+i&e81 -n!e "un! +e i*es+ c"ncen+r-+i"ns in y$e 2 PrPc(129') (Hi*. 1).92 ebr"-! r-n*e " -bs"lu+e -n! rel-+i&e le&els " rPrPc -n! sPrPc "erse&i!ence " - br"-! s$ec+ru " PrPc "lecules !ierin* in $r"+e-sesensi+i&i+y in e-c *r"u$ i+ -n i!en+ic-l $"ly"r$is -+ c"!"n 129 " +e

PM>P *ene -n! -n i!en+ic-l $-++ern. '"re"&er +ese <n!in*s si*n-l +eeGis+ence " - &-rie+y " sJI PrPc c"n"rers; -n! since $r"+e-sesensi+i&i+y is "ne " +e c-r-c+eris+ics " $ri"n s+r-ins +ey -ls" su**es+ +-+!is+inc+ sJI $ri"n s+r-ins eGis+.56578182104105<*ure $ri"6108*1Hi*ure 1. e rel-+i"nsi$ be+een !ur-+i"n " +e !ise-se (le+ $-nel)c"ncen+r-+i"n -n! (ri*+ $-nel) c"n"r-+i"n-l s+-bili+y " sPrPc c"n"rersin sJI $-+ien+s i+ !ieren+ $-++erns -n! PM>P *ene $"ly"r$iss.92

e s+-bili+y " ...

e e+er"*enei+y " PrPc c"n"r-+i"ns e "un! i+ I= i+in sJI$-+ien+s ""y*"us "r c"!"n 129 $ly"r$is " +e PM>P *ene isre-r-ble -&in* - r-n*e c"rres$"n!in* +" +-+ " s+-bili+ies "un! in-$$r"Gi-+ely 30 !is+inc+ s+r-ins " !en"&" -n! n-+ur-l l-b"r-+"ry r"!en+$ri"ns s+u!ie! u$ +" n".567292106 e in+ri*uin* !ieren+i-l eec+ " PL+re-+en+ i+ incre-sin* s+-bili+y " +y$e 1 -n! !ecre-sin* s+-bili+y " y$e 2PrPc(129') su**es+s +-+ in c"n+r-s+ +" y$e 1 +e $r"+e-seresis+-n+ c"re" y$e 2 -s $r""un!ly !es+-bilie!. "*e+er i+ +e incre-se! reAuency" eG$"se! e$i+"$es in c"!"n 129 '' s-$les i+ y$e 2 rPrPc -+er PL+re-+en+ +ese "bser&-+i"ns -y in!ic-+e "ne " +ree $"ssibili+ies: +-+ +eli*-n! $r"+ec+in* +e 3H4 e$i+"$e -s re"&e! by PL +re-+en+; +-+ e$i+"$e108–112 -s $r"+ec+e! by +e >+erinus " PrPc; "r +-+ c"n"r-+i"n-l+r-nsi+i"n resul+e! in "re eG$"se! 108–112 e$i+"$e. e+er +e e$i+"$ein!r-nce in un!i*es+e! PrPc is +e resul+ " li$i! *lyc"s-in"*lyc-nnucleic -ci! "r $r"+ein bin!in* +" +e c"n"rers uniAue +" +e ''2 sJIHPrPc re-ins +" be es+-blise!. ince sJI c-ses i+ y$e 2 PrPc(129')-&e re-r-bly eG+en!e! !ise-se !ur-+i"ns +e "lecul-r ec-nisun!erlyin* +ese eec+s c-lls "r !e+-ile! in&es+i*-+i"n. uul-+i&ely "ur<n!in*s in!ic-+e +-+ sJI PrPc eGibi+s eG+ensi&e c"n"r-+i"n-le+er"*enei+y -n! su**es+ +-+ - i!e s$ec+ru " sJI $ri"ns c-use +e!ise-se. e+er +is e+er"*enei+y "ri*in-+es in - s+"c-s+ic is"l!in*$r"cess +-+ *ener-+es -ny !is+inc+ selre$lic-+in* c"n"r-+i"ns3762 "r



in - c"$leG $r"cess " e&"lu+i"n-ry selec+i"n !urin* !e&el"$en+ " +e!ise-se73 re-ins +" be es+-blise!.

e !isc"&ere! $r"+e-sesensi+i&e c"n"rers " PrPc ile !e&el"$in* -c"n"r-+i"n!e$en!en+ iun"-ss-y (I=) ic !"es n"+ reAuire$r"+e"ly+ic !e*r-!-+i"n " ubiAui+"us PrP 56. #l+"u* +e "ri*in-l !e<ni+i"n

" sPrPc -s $urely "$er-+i"n-l c"nsi!er-ble -!!i+i"n-l !-+- !e"ns+r-+e+-+ (1) sPrPc re$lic-+es in &i&" -n! in &i+r" -s -n in&-ri-n+ -n! -F"rr-c+i"n " PrPc; (2) sPrPc se$-r-+es r" rPrPc in i* s$ee!cen+riu*-+i"n -n! (3) +e $r"+e"ly+ic sensi+i&i+y " PrPc c-n reli-bly!ieren+i-+e &-ri"us $ri"n s+r-ins.56578182104105 #ccuul-+i"n "sPrPc $rece!es $r"+e-seresis+-n+ $r"!uc+ (rPrPc) in $ri"n inec+i"n64107;-n! u$ +" 90Q " PrPc -ccuul-+in* in JI br-ins c"nsis+s " sPrPc 81.

us +e !e+ec+i"n by I= " sPrPc -s - !ise-ses$eci<c -rer is i!elyre*-r!e! -s - "re reli-ble b-sis "r !i-*n"sin* $ri"n !ise-ses. isi$r"&e! !e+ec+i"n le! +" +e !isc"&ery " - ne u-n $ri"n !is"r!er&-ri-bly $r"+e-sesensi+i&e $ri"n"$-+y (VPPr).17568190108 =+ isn"+e"r+y +-+ syn+e+ic $ri"ns *ener-+e! in &i+r" !urin* $"lyeri-+i"n "

rec"bin-n+ "use PrP in+" -yl"i! <bers $r"!uce! $ri"ns c"$"se!eGclusi&ely " sPrPc u$"n in"cul-+i"n in+" il! ice.106

Kur recen+ !-+- in!ic-+e +-+ +e le&els -s ell -s s+-bili+y " sPrPc -re -*""! $re!ic+"r " +e $r"*ressi"n r-+e in sJI (Hi*. 1).92 Ies$i+e +eine&i+-ble inuence " &-ri-ble *ene+ic b-c*r"un! -n! +e $"+en+i-l!iBcul+ies in e&-lu-+in* ini+i-l sy$+"s +e !ise-se $r"*ressi"n r-+e -n!incub-+i"n +ie F"in+ly re$resen+ -n i$"r+-n+ $-r-e+er ic is inuence!by re$lic-+i"n r-+e $r"$-*-+i"n -n! cle-r-nce " $ri"ns r" +ebr-in.64109 e c"rrel-+i"ns -"n* +e le&els " sPrPc +e s+-bili+y "sPrPc -n! +e !ur-+i"n " +e !ise-se "un! in +is s+u!y -ll in!ic-+e +-+sPrPc c"n"rers $l-y -n i$"r+-n+ r"le in +e $-+"*enesis. en sPrPc isless s+-ble +-n rPrPc +e !ierence in s+-bili+y c"rrel-+es i+ less-ccuul-+e! sPrPc -n! s"r+er !ur-+i"n " +e !ise-se. "n&ersely ensPrP c"n"rers -re "re s+-ble +-n rPrPc e "bser&e! +e "$$"si+e eec+?"re -ccuul-+e! sPrPc -n! eG+en!e! !ise-se !ur-+i"n (Hi*. 1).

=n l-b"r-+"ry r"!en+ $ri"n "!els e "un! +-+ le&els " sPrPc &-rie! i++e incub-+i"n +ie " +e !ise-se56 -n! e y$"+esie! +-+ +e "lecul-rec-nis " +is lin -y be rel-+e! +" +e re$lic-+i"n "r cle-r-nce r-+e "$ri"ns.566481 Kur recen+ !-+- "n sJI $ri"ns eG+en! +is "bser&-+i"n -n!in!ic-+e +-+ i*er le&els " less s+-ble sPrPc le-! +" -s+er $r"*ressi"n "+e !ise-se.92 ese "bser&-+i"ns -re in -cc"r! i+ +e eG$erien+s "nye-s+ $ri"ns -n! su**es+ +-+ +e s+-bili+y " is"l!e! $r"+ein is in&erselyrel-+e! +" +e re$lic-+i"n r-+e.110 #l+"u* +e "!ul-+in* eec+ " $ri"ncle-r-nce in +e --li-n br-ins is liely64 +e !-+- r" b"+ ye-s+ -n!u-n $ri"ns le-! +" +e y$"+esis +-+ +e less s+-ble $ri"ns re$lic-+e-s+er by eG$"sin* "re -&-il-ble si+es "r *r"+ " +e -**re*-+es. =n--li-n $ri"ns +is eec+ le-!s +" s"r+er incub-+i"n +ie -n! -s+er$r"*ressi"n " +e !ise-se." +":Hu+ure !irec+i"ns



#!!i+i"n-l s+e$s -re necess-ry +" i$r"&e "ur un!ers+-n!in* " +e$en"+y$ic !i&ersi+y " sJI. Kne s+e$ is +" !e+erine e+er +e iGe! $-++erns " y$e 1–2 rPrPc in +e s-e "r !ieren+ -n-+"ic-l -re-sre$resen+ - uniAue c"n"r-+i"n "r - iG+ure " c"n"rers -n! +" -$ +e!is+ribu+i"n in +e in!i&i!u-l br-in.89 #!!i+i"n-lly n"&el c"n"r-+i"n-l

-$$r"-ces usin* +-n!e $r"+ein is"l!in* cyclic -$li<c-+i"n (P'#) -n!I= s"ul! -ll" -n-lysis " +e i$-c+ " !ieren+ PrPc $"ly"r$iss -n!c"n"r-+i"ns "n +e re$lic-+i"n r-+e " u-n $ri"ns. uc s+u!ies -&ecle-rly br"-!er i$lic-+i"ns -s recen+ !-+- su**es+ +-+ +e $r"cess "in+ercellul-r in!uc+i"n " $r"+ein is"l!in* is rele&-n+ in +e $-+"*enesis "*r"in* nuber " "+er neur"!e*ener-+i&e !ise-ses.3943" +":#cn"le!*en+s

e -u+"rs +-n Pierlu*i -be++i -n! i+"l! ureic "r enc"ur-*een+-n! s+iul-+in* !iscussi"ns. is "r -s su$$"r+e! by *r-n+s r" >=# (#14359) >=>I (>074317) I (EM8%E515004) -n! +e -rles .

ri++"n Hun!." +":l"ss-ry#bbre&i-+i"ns:

#, -y"+r"$ic l-+er-l scler"sisI= c"n"r-+i"n!e$en!en+ iun"-ss-yJI reu+el!+J-"b !ise-se ers+-nn+r]usslerceiner syn!r"ePrP $ri"n $r"+einPrP n"r-l "r cellul-r $ri"n $r"+einPrPc $-+"*enic $ri"n $r"+einPM>P $ri"n $r"+ein *enerPrPc $r"+e-seresis+-n+ c"n"rers " $-+"*enic $ri"n $r"+einsPrPc $r"+e-sesensi+i&e c"n"rers " $-+"*enic $ri"n $r"+einsJI s$"r-!ic reu+el!+J-"b !ise-seH= s$"r-!ic -+-l ins"ni-VPPr &-ri-ble $r"+e-sesensi+i&e $ri"n"$-+y



" +":H""+n"+es

Pre&i"usly $ublise! "nline:.l-n!esbi"science.c"%F"urn-ls%$ri"n%-r+icle%18666

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#r+icles r" Pri"n -re $r"&i!e! ere c"

Jurnal 1

Prion. 2010 E$t#e$; >(>): 265–27>.Publi!e" online 2010 E$tober 1. "oi: 10.>161&pri.>.>.1%125PM#: PM%268959

Nanoimaging for prion related diseases

AleLe = r+nolobo"te@, 1 AleL+n"er M Portillo,1 +n+ #e$ertG+u"i',2 =oler

#e$ert,2,% +n" Yuri 3 3ub$!eno 1


Abstract

Mi?ol"in' +n" +''re'+tion o? prion protein i line" to + number o? neuro"e'ener+ti@e"ior"er u$! + reut<?el"t-+$ob "ie+e (-#) +n" it @+ri+nt: uru, Gertm+nn*tr+uler*$!einer n"rome +n" ?+t+l ?+mili+l inomni+. n prion "ie+e, in?e$tiou

p+rti$le +re protein t!+t prop+'+te b tr+nmittin' + mi?ol"e" t+te o? + protein, le+"in'to t!e ?orm+tion o? +''re'+te +n" ultim+tel to neuro"e'ener+tion. Prion p!enomenon inot retri$te" to !um+n. !ere +re + number o? prionrel+te" "ie+e in + @+riet o?m+mm+l, in$lu"in' bo@ine pon'i?orm en$ep!+lop+t! (/*, +lo no4n + m+" $o4"ie+e) in $+ttle. All no4n prion "ie+e, $olle$ti@el $+lle" $r'n%("%%"-!& %pon"or(

&n#&p'!op'$"&% (*), +re untre+t+ble +n" ?+t+l. Prion protein 4ere +lo ?oun" inome ?un'i 4!ere t!e +re reponible ?or !erit+ble tr+it. Prion protein in ?un'i +ree+il +$$eible +n" pro@i"e + po4er?ul mo"el ?or un"ert+n"in' t!e 'ener+l prin$ipleo? prion p!enomenon +n" mole$ul+r me$!+nim o? m+mm+li+n prion "ie+e.Preentl, e@er+l ?un"+ment+l Duetion rel+te" to prion rem+in un+n4ere". oreL+mple, it i not $le+r !o4 prion $+ue t!e "ie+e. Et!er unno4n in$lu"e t!e n+ture+n" tru$ture o? in?e$tiou +'ent +n" !o4 prion repli$+te. Gener+ll, t!e p!enomenon o?mi?ol"in' o? t!e prion protein into in?e$tiou $on?orm+tion t!+t !+@e t!e +bilit to prop+'+te t!eir propertie @i+ +''re'+tion i o? i'ni?i$+nt interet. #epite t!e $ru$i+limport+n$e o? mi?ol"in' +n" +''re'+tion, @er little i $urrentl no4n +bout t!emole$ul+r me$!+nim o? t!ee pro$ee. !ile t!ere i +n +pp+rent $riti$+l nee" totu" mole$ul+r me$!+nim un"erlin' mi?ol"in' +n" +''re'+tion, t!e "et+ile"$!+r+$teri<+tion o? t!ee in'le mole$ule pro$ee i !in"ere" b t!e limit+tion o?$on@ention+l met!o". Alt!ou'! ome iue rem+in unreol@e", mu$! pro're !+ been


http://www.ncbi.nlm.nih.gov/pubmed/?term=Krasnoslobodtsev%20AV%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Portillo%20AM%5Bauth%5D



http://www.ncbi.nlm.nih.gov/pubmed/?term=Deckert-Gaudig%20T%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Deckert%20V%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Lyubchenko%20YL%5Bauth%5D









http://www.ncbi.nlm.nih.gov/pubmed/?term=Krasnoslobodtsev%20AV%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Deckert-Gaudig%20T%5Bauth%5D



http://www.ncbi.nlm.nih.gov/pubmed/?term=Lyubchenko%20YL%5Bauth%5D








re$entl m+"e prim+ril "ue to t!e +ppli$+tion o? n+noim+'in' tool. !e ue o?n+noim+'in' met!o" !o4 're+t promie ?or un"ert+n"in' t!e mole$ul+r me$!+nimo? prion p!enomenon, poibl le+"in' to4+r" e+rl "i+'noi +n" e??e$ti@e tre+tment o?t!ee "e@+t+tin' "ie+e. !i re@ie4 +rti$le umm+ri<e re$ent report 4!i$! +"@+n$e"our un"ert+n"in' o? t!e prion p!enomenon t!rou'! t!e ue o? n+noim+'in' met!o".

/ey words4 protein mi?ol"in', prion, +tomi$ ?or$e mi$ro$op, n+nome"i$ine, ?or$epe$tro$opGo to:

&tructure of Amyloid

*i'ni?i$+nt pro're !+ been m+"e in un"ert+n"in' t!e tru$ture o? +''re'+te" pe$ie+t t!e +tomi$ le@el uin' bot! $omput+tion+l mo"elin' +n" eLperiment+l tu"ie u$! +^r+ $rt+llo'r+p! +n" oli"t+te M. t i 4i"el +$$epte" t!+t t!e in?e$tiou ?ormo? prion i el?prop+'+tin' ?ibrill+r or +mloi" PrP.1 !e ?orm+tion o? +mloi" !+ been

ti'!tl line" to t!e "e@elopment o? t!e "ie+e. Amloi" !+re $ommon tru$tur+l?e+ture +n" biop!i$+l propertie, in$lu"in' bin"in' o? pe$i?i$ "e, elon'+te"morp!olo' +n" nu$le+tion"epen"ent ineti$ o? +''re'+tion. /+e" on oli"t+te M +n" ^r+ $rt+llo'r+p! "+t+, t!e un"erlin' tru$ture o? prion +mloi" 4+ ?oun" to!+re $ommon tru$tur+l ?e+ture. !e $ont+in imil+rl +rr+n'e" p+r+llel !eet p+$e" in re'iter ?or u$! "i??erent prion protein + re2p189 (t!e b+i o? t!e I%J prion),2 re2p10%9,% *up%5p (I PSI [J prion),> nD1p (I PIN [J prion).5 Gener+ll, bet+tr+n" o? + protein mole$ule run perpen"i$ul+r to t!e +Li o? t!e ?ibril +n" !"ro'en bon"in' in u$! tru$ture o$$ur +lon' t!e ?ibril +Li. Et!er mo"el, !o4e@er, nee" to be$oni"ere" + ome report u''et t!+t t!e p+r+llel inre'iter tru$tur+l mo"el o?+mloi" ?+ile" to eLpl+in eLperiment+l ober@+tion o? t!e "i@erit o? tr+inpe$i?i$

morp!olo'ie o? t!e *up%5 +mloi" ?ibril.6

Go to:

&mall %lements Go7ern Prion Aggregation

!e +bo@e"e$ribe" t!eme o? tru$tur+l or'+ni<+tion o? ?ibril eem r+t!er $ommon int!e ?orm+tion o? +mloi". *!ort e'ment o? ot!er nonprion +mloi" protein]+mloi",7,8 wnu$lein,9,10 ilet +mloi" polpepti"e (APP),11 lo<me12 +n" 2mi$ro'lobulin1% ]+re $+p+ble o? ?ormin' +mloi" ?ibril. t i re+on+ble to +ume t!+t

t!e n+ture o? +mloi"o'eni$ re'ion m+ be "e"u$e" ?rom t!e repe+tin' ?ol"in' moti? int!e +mloi" ?ibril. n$re+in' e@i"en$e in"i$+te more +n" more t!+t t!e buil"in' blo$o? +mloi" ?ibril +re !ort ?r+'ment o? t!e entire protein eDuen$e. !i u''et t!+tt!e +''re'+tion m+ be'in 4it! onl + !ort e'ment o? t!e entire protein eDuen$e. An$!+n'e in en@ironment+l $on"ition t!+t: (1) open + n+ti@e protein $on?orm+tion,eLpoin' t!i p+rt o? t!e eDuen$e, +n"&or (2) timul+te $on?orm+tion+l $!+n'e to +n+''re'+tionprone t+te, $oul" ?+$ilit+te t!e +''re'+tion pro$e. !e +bo@ementione"eL+mple upport re$entl propoe" +mloi" tret$! !pot!ei. !e !pot!ei u''et







































t!+t + !i'!l +mloi"o'eni$ !ort +mino +$i" tret$! m+ tri''er t!e el?+embl pro$e o? + protein into +''re'+te.1>,15 nter+$tion bet4een pe$i?i$ protein re'ion?+$ilit+te t!e neLt tep in t!e ?orm+tion o? + mi?ol"e" $on?orm+tion. !ee re'ion +reno4n + +''re'+tion !ot re'ion,16,17 4!i$! +re !ort tret$!e o? + prim+r proteineDuen$e.

An ele'+nt +ppro+$! to re$o'ni<e u$! m+ll element o? + prim+r eDuen$e t!+tnu$le+te +n" promote +''re'+tion o? prion protein *up%5 4+ re$entl utili<e".18 An +rr+o? o@erl+ppin' pepti"e 20 +mino +$i" in len't! "eri@e" ?rom t!e eDuen$e o? t!e prion*up%5 4ere $o@+lentl +tt+$!e" to + 'l+ li"e. Pepti"e 4ere printe" onto t!e ur?+$e10–12 nm +p+rt ?rom e+$! ot!er, pro@i"in' !i'! reolution +n" retri$tin' el?inter+$tion. !ee pepti"e +rr+ 4ere in$ub+te" 4it! ?luore$entl l+bele" ?ull len't! M *up%5. !e +$$umul+tion o? ?luore$en$e 4+ ober@e" +?ter 2 !our o? in$ub+tion +t+ @er m+ll et o? imprinte" pepti"e +mino +$i" 9–%9 +n" 90–120. !ee eDuen$e lie4it!in t!e re'ion 4!i$! 4ere pre@ioul i"enti?ie" to be in el?$ont+$t 4it!in m+ture?ibril.19 *u$! + n+no+rr+ +ppro+$! in"i$+te" t!+t t!ee m+ll re'ion +re not onl ite

o? intermole$ul+r $ont+$t in m+ture ?ibril, but t!e +lo 'o@ern el?re$o'nition 4it!inoluble nonprion $on?ormer 4it! !i'! pe$i?i$it. !ere?ore, m+ll tret$!e o? proteineDuen$e +re u??i$ient to "ri@e t!e $on@erion o? ?ulllen't! M ?rom nonprion t+teinto el?templ+tin' +mloi" $on?orm+tion.18 *ometime + $ompleL inter+$tion +mon'm+ll re$o'nition element i reDuire" ?or prion prop+'+tion. or eL+mple, ?our O ri$!"om+in o? nD1 $+n in"epen"entl tr+nmit t!e prion t+te but +$t $ooper+ti@el to+tt+in t!e ?in+l prion $on?orm+tion.20 !e eLiten$e o? tr+nmiion b+rrier +lo i+??e$te" b t!e $ooper+ti@e +$tion o? +ll ?our prion "om+in o? nD1.20 *e@er+l ot!er lineo? e@i"en$e +lo point to $ompleL inter+$tion 4it!in prion protein ?or t!e ?orm+tion o?tr+in. E!!+!i et +l.21 re$entl reporte" t!+t tr+nient nonn+ti@e inter+$tion outi"e t!ere$o'nition element +re import+nt in "eterminin' temper+ture"epen"ent tr+in

$on?orm+tion o? *up%5.

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"irect !bser7ation of 3ibril Growth

Alt!ou'! $on@in$in' tru$tur+l mo"el o? +mloi" ?ibril !+@e re$entl emer'e", t!eno4le"'e o? pre$ie ineti$ me$!+nim o? ?ibril ?orm+tion 4oul" 're+tl bene?it ourun"ert+n"in' o? t!e prion p!enomenon. o@el tool 4!i$! en+ble t!e "ire$t ober@+tiono? in"i@i"u+l ?ibril 'ro4t! +re import+nt not onl ?or obt+inin' ?urt!er ini'!t into t!eme$!+nim o? protein el?+o$i+tion but +lo ?or i"enti?in' $ompoun" t!+t in!ibit

?ibril 'ro4t!. e$ent +"@+n$e in in'le mole$ule met!o" o??ere" b t!e +tomi$ ?or$emi$ro$op +n" in'le mole$ule ?luore$en$e mi$ro$op +llo4e" t!e monitorin' o?+''re'+tion +t t!e le@el o? in"i@i"u+l ?ibril pro@i"in' in?orm+tion +bout t!e r+te +n""ire$tion o? 'ro4t!.

!e in'le?ibril 'ro4t! o? M *up%5 4+ eL+mine" uin' tot+l intern+l re?le$tion?luore$en$e mi$ro$op ().22 5l+bele" ee" 4ere +tt+$!e" to + 'l+ li"e @i+ biotintrept+@i"in lin+'e. !e %l+bele" monomer M 4+ +""e" to t!e olution.



































!e +""ition o? in"i@i"u+l %l+bele" mole$ule $oul" be re+"il "ete$te" +t t!e en" o? 5l+bele" ?ibril. in' u$! +n eLperiment+l etup, 4!ere me+urement $oul" ?ollo4t!e ?luore$en$e intenitie o? t!e +""ition e@ent, m+"e it poible to "etermine !o4m+n mole$ule +re +""e" "urin' + in'le e@ent. !e "+t+ et+bli!e" t!+t t!e ?ibril'ro4t! pro$ee" @i+ +""ition o? M monomer onto ?ibril en", pro@i"in' +""ition+l

e@i"en$e ?or t!e me$!+nim o? ?ibril 'ro4t!. Ho4e@er, u$! eLperiment reDuire"l+belin' o? protein 4it! "e mole$ule, +n" t!e intro"u$tion o? t!e l+bel mi'!t inter?ere4it! +''re'+te ?orm+tion +n"&or me+urement.

Anot!er met!o" !+ been intro"u$e" to monitor t!e ?orm+tion pro$e o? +mloi" ?ibril4it!out l+belin' o? + protein mole$ule.2% !e ue o? +mloi"?ibril pe$i?i$ "e !io?l+@in (!) ?luore$en$e in $ombin+tion 4it! tot+l intern+l re?le$tion ?luore$en$emi$ro$op (M) en+ble" + "ire$t ober@+tion o? t!e +mloi" ?ibril 'ro4t! in re+ltime.2% – 25 o +""ition+l ?luorop!ore l+belin' 4+ reDuire" to @iu+li<e ee""epen"ent+mloi" ?ibril 'ro4t! o? 2m,2% or A1–>0,2>,25 +t t!e in'le ?ibril le@el.

Anot!er ue?ul tool ?or "ire$t ober@+tion o? +mloi" ?ibril 'ro4t! 4!i$! !+ been 4i"elue" i AM]+tomi$ ?or$e mi$ro$op. !e m+in +"@+nt+'e o? AM i it +bilit tomonitor on'oin' pro$ee un"er @+riou olution $on"ition 4it!out +n eLtr+ l+belin'reDuire". e$entl, AM 4+ u$$e?ull ue" to monitor t!e el?+embl o? e@er+l+mloi"o'eni$ protein,26,27 in$lu"in' +mlin +n" +mloi"bet+.28,29 An +embl o?in"i@i"u+l ?ibril ?orme" b +mloi" bet+25–%5 4+ tu"ie" b + mo"i?ie" +ppli$+tion o? t!e +tomi$ ?or$e mi$ro$op, $+nnin' ?or$e mo'r+p!.%0 !i met!o" elimin+te" t!enee" to $+n t!e 4!ole im+'e b $+nnin' ?ibril onl. *u$! +n impro@ement i'ni?i$+ntlin$re+e" t!e tempor+l reolution 4it! 4!i$! t!e ober@+tion o? in'le ?ibril elon'+tion pro$e i me+ure". in' t!i met!o", ellerm+er et +l.%0 !+@e "etermine" t!+t t!e+embl o? t!e ?ibril i pol+ri<e" +n" "i$ontinuou. !e +mloi" +embl pro$ee"e"

@i+ r+pi" burt o? 'ro4t! t!+t eLten"e" t!e ?ibril b 7 nm or it inte'er multiple.

%0

!e'ro4t! p!+e 4ere ?ollo4e" b p+ue in + tep4ie m+nner, u''etin' + ?lu$tu+tion o?+mloi" t+te in 4!i$! 'ro4t! m+ be eit!er permitte" or in!ibite".

A in'le ?iber 'ro4t! ++ 4+ ue" to eL+mine t!e !etero'eneit o? +mloi" ?ibril?orme" b t!e e+t *up%5 prion protein. !i ++ ue" t4o @+ri+nt o? t!e *up%5 t!+t4ere "i??erenti+ll l+bele" +n" "itin'ui!e" b AM. !e t4o @+ri+nt "i??ere" in t!eir+bilit to bin" +n +ntibo", pro@i"in' + me+n o? i"enti?i$+tion o? one tpe o? t!e protein b AM be$+ue bin"in' t!e +ntibo" in$re+e t!i$ne o? t!e ?iber %?ol". !i tu"?oun" t!+t *up%5 pont+neoul ?orm multiple +n" "itin$t ?ibril tpe. !ee tpe"i??er b t!e "e'ree o? pol+rit +n" o@er+ll 'ro4t! r+te, u''etin' + 're+t @+ri+tion in propertie o? t!e ?ibril. !e ober@e" "i@erit eem to be 4elluite" to +$$ount ?or t!er+n'e o? prion tr+in p!enotpe.%1

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Polymorphism and Prion &trains








































Amloi" ?ibril 'ener+ll eL!ibit imil+r +ppe+r+n$e in + ?orm o? elon'+te", unbr+n$!e"tru$ture. *e@er+l unrel+te" protein u$! + inulin, +mloi" bet+ +n" +mlin $+n ?orm+lmot i"enti$+l morp!olo'ie. A''re'+te" prion protein +lo eL!ibit imil+r +mloi"?ibril +ppe+r+n$e. #epite t!e 'ener+l imil+rit o? +''re'+te" pe$ie, o?ten + miLture o? ?ibril 4it! @+riou morp!olo'ie i ?orme". Moreo@er, ?ibril o? t!e +me polpepti"e

eDuen$e $+n ?orm "itin$t morp!olo'ie eL!ibitin' + 're+t 4e+lt! o? polmorp!im.

3igure 1 !o4 AM im+'e o? ?ibril ?orme" b t!e GOOY pepti"e in "i??erenten@ironment+l $on"ition. *imple @+ri+tion in t!e en@ironment u$! + pH +n" ioni$tren't! o? olution, temper+ture +n" me$!+ni$+l tre (?or eL+mple, +'it+tion) $+n reultin t!e ?orm+tion o? ?ibril 4it! "i??erent $!+r+$teriti$. Moreo@er, prion protein +re$+p+ble o? ?ormin' +''re'+te 4!i$! "i??er in t!eir p+ttern o? prote+e reit+n$e +n"tr+nmiibilit. !e "i??eren$e in t!ee propertie o? +''re'+te i 'ener+ll re?erre" to+ prion tr+in. n tr+nmiible pon'i?orm en$ep!+lop+t!ie, "itin$t p!enotpe o? +"ie+e $orrepon" to "i??erent prion tr+in.%2

i'ure 1*$!eme illutr+tin' t!+t + protein mole$ule $+n +"opt e@er+l $on?orm+tion+l t+te 4!i$!m+ reult in +''re'+te o? "i??erent morp!olo'ie. AM im+'e o? GOOY pepti"e ?rom *up%5 e+t prion protein +''re'+te" 4it! t!e ?orm+tion o? ?ibril o?"itin$t )))

!e p!enomenon o? prion tr+in implie t!+t t!ere eLit +n enemble o? "itin$t

prop+'+tin' $on?orm+tion ?or + in'le polpepti"e eDuen$e. !ere?ore, +''re'+tion o? polpepti"e mi'!t pro"u$e e@er+l "itin$t polmorp! "epen"in' on initi+l mi?ol"e"$on?orm+tion. !e "n+mi$ n+ture o? t!e $on?orm+tion+l p+$e, t!e $ompleLit o?rel+tion!ip bet4een tr+in +n" t!e potenti+l to 'ener+te + l+r'e number o? ne4 priontr+in poe + $riti$+l nee" ?or +""rein' t!ee iue. !e 're+t 4e+lt! o? polmorp!im +n" "i@erit o? prion tr+in preent + eriou ri ?or publi$ !e+lt!.%%

n"i@i"u+l ?ibril +re 'ener+ll $oni"ere" to be tru$tur+ll uni?orm, m+int+inin' t!e+me tru$ture o@er t!e len't! o? t!e ?ibril. t i belie@e" t!+t t!e morp!olo' +n"tru$ture o? pre?orme" ee" i prop+'+te" in + templ+telie m+nner, p+in' t!e$!+r+$teriti$ o? templ+te]morp!olo', tru$ture +n" in?e$ti@it]to t!e neLt

'ener+tion o? +''re'+te.%> – %6

*u$! !erit+bilit i o tron' t!+t ee" prop+'+te t!eir$!+r+$teriti$ e@en 4!en $on"ition +re $!+n'e" to ?+@or "i??erent $on?orm+tion+lt+te.%7

e$ent report, !o4e@er, u''et t!+t ?ibrill+r tru$ture +re $ompoe" o? proteinmole$ule t!+t !+@e "i??erent e$on"+r tru$ture.%8,%9 A $riti$+l nee" ?or i"enti?in'(probin') t!e $on?orm+tion 4it!in !etero'eneou +mple !+ been re$entl!i'!li'!te".%9 t i be$omin' $le+r t!+t t!ere i + $oeLiten$e o? multiple tr+in or

























ubtpe o? t!e "ie+erel+te" protein in +''re'+te. *u$! $on?orm+tion+l !etero'eneitm+ reult in @+riou "ie+e.

A no@el immuno$on?orm+tion+l ++ (or "u+l $olor ++) b+e" on pe$i?i$ +ntibo"iel+bele" 4it! "i??erent "e !+ been utili<e" to re@e+l tru$tur+l !etero'eneit o? PrP

prion protein 4it!in + in'le ?ibril.%9

!i tu" !o4e" t!e eLiten$e o? t!e$on?orm+tion+l !etero'eneit +$ro t!e popul+tion o? ?ibril + 4ell + 4it!in in"i@i"u+l?ibril.

e$ent ^r+ $rt+llo'r+p! +n" M tru$tur+l tu"ie emer'e" to u''et tron'lt!e ori'in o? polmorp!i$ @+ri+tion. Multiple l+er o? bet+!eet +re $loel p+$e" to$re+te +mloi" tru$ture. #i??eren$e in t!e p+$in' o? t!ee bet+!eet, ori'in+tin'?rom i"e$!+in p+$in', re'iter or topolo' o? bet+!eet, m+ eLpl+in morp!olo'i$+l@+ri+nt o? ?ibrill+r tru$ture. *oli"t+te M tu"ie $le+rl !o4e" t!e $oeLiten$e o?t!ree "itin$t $on?orm+tion o? t!e GOOY pepti"e 4it!in + in'le ?ibril.%8 #i??erent p+$in' +rr+n'ement o? pepti"e 4it!in + ?ibril 4ere propoe" to be reponible ?or t!e

ober@e" "i??eren$e in M $!emi$+l !i?t. !ee $oeLitin' $on?orm+tion "i??er bt!e "e'ree o? lo$+l e$on"+r tru$ture (+lp!+ !eli$+l @eru bet+ !eet). %8 e$ent$rt+llo'r+p!i$ tu"ie !+@e i"enti?ie" e@er+l (8) $l+e o? o$+lle" teri$ <ipper.9 #epite t!e ?un"+ment+l imil+ritie in t!e tru$ture 4it! eLten"e" protein tr+n" t!+t +re perpen"i$ul+r to t!e +Li o? bet+ !eet, t!ee $l+e @+r in t!e b+i$ teri$ <ippertru$ture. *u$! @+ri+tion in@ol@e m+inl orient+tion o? pepti"e +n" bet+!eet 4it!repe$t to e+$! ot!er. t 4+ ?oun" t!+t ome pepti"e 4ere $+p+ble o? ?ormin' "i??erent polmorp! 4it! re'+r" to t!eir b+i$ teri$ <ipper tru$ture, o??erin' + poibleeLpl+n+tion ?or +mloi" polmorp!im +n" prion tr+in.9

#ue to t!e "i??i$ult o? "eterminin' t!e tru$ture o? +mloi" +n" t!e potenti+l ?or

tru$tur+l !etero'eneit 4it!in + in'le ?ibril, one +ppre$i+te t!e "e@elopment o? no@elmet!o" t!+t $oul" pro@i"e in?orm+tion +bout t!e morp!olo' o? +''re'+te + 4ell +t!eir un"erlin' $on?orm+tion+l "i??eren$e. !ee met!o" +re $urrentl emer'in' + +$ombin+tion o? AM +n" @ibr+tion+l pe$tro$op (in?r+re" +borption or +m+npe$tro$op) $+p+ble o? re$o'ni<in' t!e e$on"+r tru$ture o? protein. +n" +m+n$+tterin' !+@e re$entl ?oun" + 4i"e +ppli$+tion in $!+r+$teri<+tion o? +mloi".>0 – >% Eneo? t!e bi''et +"@+nt+'e o? u$! $ombine" met!o" i t!+t @ibr+tion+l propertie $+n beober@e" imult+neoul 4it! t!e topo'r+p!i$ im+'e. An +""ition+l +"@+nt+'e i t!+t t!e probin' o? !etero'eneou +mple i poible.

Ene re$ent illutr+ti@e eL+mple i + $ombin+tion o? AM +n" ne+r?iel" in?r+re"mi$ro$op.>>,>5 Aperturele ne+r?iel" $+nnin' in?r+re" mi$ro$op (A*M) 4+utili<e" to tu" t!e morp!olo' +n" e$on"+r tru$ture o? in"i@i"u+l +mloi" ?ibril o? bet+2 mi$ro'lobulin. ouplin' ne+r?iel" in?r+re" pe$tro$op 4it! AM +llo4e" t!e$orrel+tion o? ?ibril morp!olo' +n" un"erlin' e$on"+r tru$ture. t 4+ ober@e"t!+t t!e +mple eL!ibite" + !etero'eneou popul+tion o? ?ibril: ome ?ibril !+" p+r+llel+n" ome +ntip+r+llel bet+ !eet +rr+n'ement.























Ene "i+"@+nt+'e o? A*M i it limit+tion to onl + ?e4 ele$te" 4+@elen't!. !i $+niel" to mile+"in' interpret+tion i? +n im+'e $ontr+t o? onl one or t4o ele$te"4+@elen't! i $oni"ere". E@erl+ppin' ?e+ture o? uneLpe$te" b+n", li'!t b+n" 4it!$!+n'e or !i?t $+n t!ere?ore e+il poil +n interpret+tion. n or"er to o@er$ome t!i!ort$omin', + ?ull pe$trum i reDuire", but t!i i onl poible 4it! op!iti$+te"

eDuipment +t n$!rotron our$e.

A rel+te" +ppro+$! t!+t +llo4 tu"ie o? t!e e$on"+r tru$ture o? ?ibril i re+li<e" btipen!+n$e" +m+n $+tterin' (*).>6 – >8 n *, +n AM or *M ($+nnin'tunnelin' mi$ro$ope) i $ombine" 4it! + t+n"+r" +m+n mi$ro$ope in or"er to eL$ee"t!e "i??r+$tion limit +n" to in$re+e t!e eniti@it o? $on@ention+l +m+n pe$tro$op.!i i re+li<e" b +tt+$!in' + in'le il@er or 'ol" n+nop+rti$le to t!e +peL o? +n AM tipor b utili<in' +n et$!e" 4ire. *imil+r to t!e A*M +ppro+$!, @ibr+tion+l mo"e o?mole$ule un"er t!e tip eLperien$e + i'n+l en!+n$ement o? e@er+l or"er o? m+'nitu"e.or +n o@er@ie4, ee re?. >9. Gi@en t!+t * i + $+tterin' tpe o? pe$tro$op, + in'leeL$it+tion ?reDuen$ iel" + ?ull pe$trum. Hen$e, o@erl+ppin' b+n" o? uneLpe$te"

$ompoun" $+n be "itin'ui!e" e+il b multi@+ri+te t+titi$, ?or int+n$e. !iren"er * + !i'!l eniti@e met!o", 4it! e@en in'lemole$ule [email protected],51 *imult+neoul to pe$tr+ +$Duiition 4it! + l+ter+l reolution "etermine" b t!en+nop+rti$le "imenion, t!e topo'r+p! o? t!e +mple +lo i m+ppe" 4it! + p+ti+lreolution $omp+r+ble to t+n"+r" AM te$!nolo'. urt!ermore, * oper+te l+bel?ree +n" non"etru$ti@e, 4!i$! me+n t!+t t!e +mple $+n be ue" ?or + ubeDuent+n+li.

3igure 6A !o4 + tpi$+l * etup. !ree pe$tr+ o? + in'le +mloi" ?ibril ?orme"?rom + GOOY pepti"e (?r+'ment o? *up%5 e+t prion protein) +t pH 5.6 +reele$te" +n" !o4n in 3igure 6(. !e pe$tr+ 4ere re$or"e" +t eDui"it+nt (7 nm)

poition perpen"i$ul+r to t!e m+in ?ibril +Li. *in$e t!e pepti"e !+" onl + !orteDuen$e o? ei'!t +mino +$i", +ll pe$tr+ in 3igure 6( +re imil+r. !e pe$i?i$ poitiono? t!e +mi"e +n" +mi"e b+n" pro@i"e e@i"en$e o? + !eet tru$ture t!+t i t+ble int!i +re+ o? t!e ?ibril. or ?ibril 4it! @+rin' e$on"+r tru$ture, * en+ble t!e pre$ie lo$+li<+tion +n" +i'nment o? "i??erent $on?orm+tion.

i'ure 2

(A) *et$! o? + b+$ re?le$tion * etup, (/) * pe$tr+ o? + ?ibril ?orme" bGOOY pepti"e ?rom *up%5 e+t prion protein on +"+$ent point ep+r+te" b 7nm.

rom pre@iou * tu"ie on +mino +$i" it i no4n t!+t "itin$t +mino +$i" +re"itin'ui!+ble b pe$i?i$ pe$tr+l ?e+ture.52,5% n t!e preent eLperiment, +n +i'nmento? $teine () +n" troine (Y) i poible +n" $orrepon"in' i'n+l +re m+re" in t!e































pe$trum. *u$! +n +i'nment $+n "eli@er @+lu+ble in?orm+tion i? t!e ?ibril 4+ 'ener+te"?rom @+riou or e@en unno4n pepti"e.

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The Nature of an Infectious Agent

!e rel+tion!ip bet4een prion prop+'+tion p!enomenon +n" t!e ?orm+tion o? +mloi"?ibril i poorl un"ertoo". Mot no4n +mloi"?ormin' protein +re not prion +n"e@en +mloi" o? prion protein +re not +l4+ tr+nmiible.5> – 56 !ere i till + poorun"ert+n"in' o? 4! $!+n'e in t!e $on?orm+tion o? mi?o"e" protein $+n +lter t!eir p!iolo'i$+l e??e$t. e$entl propoe" !pot!ei o? ?r+n'ibilt o? +mloi" ?ibrilo??ere" +n eLpl+n+tion t!+t mi'!t $l+ri? t!i $ompli$+te" iue.57 !e me$!+ni$+l propertie o? +mloi" +n" +mloi"N propenit to bre+, 'ener+tin' ne4 ee", eem to"e?ine t!eir p!iolo'i$+l imp+$t.57 +n++ et +l.57 looe" +t t!e "i??eren$e in t!ree$on?orm+tion (tr+in) o? prion protein *up%5 ?orme" +t > (*$>), %7 (*$%7) +n"

room temper+ture (**). !ee t!ree prion tr+in "i??er b t!eir polmeri<+tion r+te+n" $+ue "itin$t $olor p!enotpe in t!e A# $olor ++. An AMb+e" in'le?iber'ro4t! ++ 4+ ue" to me+ure ?iber 'ro4t! r+te ?or t!ee t!ree "itin$t$on?orm+tion. t 4+ ?oun" t!+t "epite t!e ?+$t t!+t *$> le+" to t!e tron'et tr+in p!enotpe, it !+ t!e lo4et intrini$ ?iber 'ro4t! o? t!e t!ree $on?ormer. !e p!i$+ltren't! o? t!e $on?ormer turne" out to be "i??erent, too. !e lo4er 'ro4t! o? *$> i+$$omp+nie" b + 're+ter "e'ree o? ?r+'ment+tion upon tirrin'. AM im+'in' re@e+le"t!+t tirrin' !+ttere" *$> +mloi" into m+n m+ll ?ibril (le t!+n 100 nm). *u$!tre+tment +lo in$re+e" ee"in' e??i$ien$ $onitent 4it! l+r'er number o? ?ibril en".!e @+ri+bilit in t!e brittlene o? t!e ?ibril 4+ propoe" to repreent + m+orme$!+nim b 4!i$! t!e tren't! o? prion tr+in p!enotpe i "etermine" b

$on?orm+tion+l t+te o? t!e protein.57 t +ppe+r t!+t, in @i@o, t!e Hp10> $!+perone !elpto ?r+'ment ?ibril o? *up%5 prion protein, +n" it i +lo reponible ?or "i+''re'+tin'l+r'e protein "epoit. !i $!+perone m+ pl+ +n import+nt role in prop+'+tion o? prion be$+ue "eletion o? Hp10> !+ been "emontr+te" to elimin+te t!e in?e$ti@it o? prion(re@ie4e" in re?. 58).

e$ent tu"ie et+bli!e" + tron' $orrel+tion bet4een t!e in$ub+tion perio" o? prion"ie+e +n" $on?orm+tion+l t+bilit o? nt!eti$ prion.59,60 !e $on?orm+tion+l t+bilit o? + nt!eti$ prion ?orme" ?rom + ?ulllen't! m+mm+li+n prion protein 4+ +lo ?oun" to$orrel+te 4it! t!e m+llet poible i<e o? t!e ?r+'ment.61 3e t+ble $on?orm+tion pro"u$e" m+ller pie$e o? ?ibril upon ?r+'ment+tion, pro@i"in' +""ition+l e@i"en$e t!+t

?r+'ment+tion m+ be import+nt in tr+nmiibilit o? prion +''re'+te +n" prion "ie+e"e@elopment. *un et +l.61 +lo !o4e" t!+t w/$rt+llin, + !e+t !o$ protein (Hp), i$+p+ble o? ?r+'mentin' rPrP ?ibril.61 An +ltern+ti@e !pot!ei ?or t!e ori'in o? ?ibril bt!eir inter+$tion 4it! + ur?+$e o? $ellul+r membr+ne !+ been propoe".61

Protein +''re'+tion i + $ompleL pro$e 4!i$! pro$ee" @i+ m+n interme"i+te t+te,in$lu"in' oli'omer, proto?ibril +n" ?ibril. !ere i in$re+in' e@i"en$e t!+t t!e en" pro"u$t o? +''re'+tion]t!e ?orm+tion o? ?ibril +n" bi' +''re'+te]i not t!e m+in



































$+ue o? t!e "ie+e. !ere eLit +n un$ert+int +bout 4!+t pe$ie in t!i $ompleL+''re'+tion p+t!4+ +re reponible ?or t!i toLi$it. Alt!ou'! t!e in?e$ti@it o? prion i+o$i+te" 4it! + 4i"e r+n'e o? +''re'+te" t+te, m+ll oli'omer o? +''re'+te" prion protein !+@e been u''ete" + minim+l in?e$tiou p+rti$le. A re$ent tu" re@e+le" t!+tt!e in?e$ti@it o? PrP i t!e 're+tet ?or p+rti$le 17–27 nm in i<e, $orrepon"in' to %00–

600 #+.62

!ee oli'omeri$ p+rti$le !oul" $onit o? 1> to 28 prion monomer. !ein?e$ti@it i "e$re+e" ?or l+r'er +''re'+te +n" @irtu+ll +bent ?or oli'omeri$ ?r+$tiono? K5 mole$ule.62

!e +bo@e"e$ribe" eLperiment+l ober@+tion upport e@en more tron'l t!e ne4emer'in' @ie4 t!+t in?e$tiou +n" toLi$ pe$ie o? prion mi'!t !+@e "i??erent i"entitie1 4it! "itin$t biop!i$+l propertie.55 Alt!ou'! +mloi" ?orm o? PrP +re in?e$tiou, t!emi'!t not be toLi$.55 An in$re+in'l +$$umul+tin' bo" o? e@i"en$e u''et t!+toli'omeri$ +emblie o? +mloi" protein +re toLi$ pe$ie,6% – 67 4!ile l+r'e +''re'+te+n" ?ibril +re r+t!er inert or e@en [email protected]

!+r+$teri<+tion o? oli'omeri$ pe$ie 4it! $on@ention+l, enemble b+e" met!o" i$!+llen'in' "ue to "n+mi$ +n" tr+nient n+ture o? oli'omer. *in'le mole$ule met!o"$+n pro@i"e uniDue in?orm+tion on t!e tru$ture, ener'eti$ +n" "n+mi$ o? interme"i+tetr+nient pe$ie ?orme" "urin' initi+l t+'e o? +''re'+tion. e$entl, + "u+l$olor,in'lemole$ule ?luore$en$e te$!niDue !+ been utili<e" to loo +t t!e e+rl t+'e o?+''re'+tion o? t!e *H% "om+in o? P% in+e "urin' +''re'+tion l+' +n" 'ro4t! p!+e.69

!e tu" ?oun" t!+t t!e oli'omeri$ pe$ie ?orme" in t!e +''re'+tion re+$tion $omprie+ !etero'eneou enemble o? oli'omer 4it! t!e me"i+n i<e o? %8 S 10 mole$ule.nteretin'l, t!i t+'e o? +''re'+tion re+$tion !+ been pre@ioul ?oun" to bem+Lim+ll $totoLi$. !e inno@+ti@e $!+r+$ter o? t!e tu" i t!e +ppli$+tion o? #] t4o$olor $oin$i"en$e "ete$tion]to tu" t!e protein el?+embl pro$e. Protein

mole$ule 4ere l+bele" 4it! t4o "i??erent "e (AleL+ luor >88 +n" AleL+ luor 6>7)t!+t $+n be "ete$te" ep+r+tel. !e ?orm+tion o? oli'omer pro$ee"e" @i+ +embl o? protein in$orpor+tin' bot! tpe o? "e into +''re'+te" pe$ie. !e preen$e o?oli'omer i m+ni?ete" b imult+neou ?luore$en$e burt in bot! re" (AleL+ luor6>7) +n" blue (AleL+ luor >88) $!+nnel. !i +llo4e" reol@in' t!e in"i@i"u+l pe$ie preent "urin' t!e initi+l t+'e o? +''re'+tion pro$e. nteretin'l, t!e tu" +lo ?oun"t!+t t!e t+bilit o? oli'omeri$ pe$ie in$re+e 4it! time 4!ile t!e i<e o? oli'omert+ @irtu+ll t!e +me. Ene poible eLpl+n+tion ?or t!i e??e$t i t!+t t!e intern+l$on?orm+tion+l reor'+ni<+tion o? "ior"ere" oli'omer le+" to en!+n$e" t+bilit "urin'?ibril ?orm+tion.69 *u$! + $on$luion i in t!e line 4it! pre@ioul propoe" nu$le+te"$on?orm+tion+l $on@erion () mo"el ?or *up%5.70 mport+ntl, + re$ent tu" o? l+$to'lobulin +''re'+tion propoe" + imil+r me$!+nim o? ?ibril ?orm+tion.69 Eli'omer!oul" un"er'o + $riti$+l $on?orm+tion+l $!+n'e to be$ome nu$le+tin' oli'omer t!+tee" +mloi" ?orm+tion. !e i<e o? u$! nu$le+tin' oli'omer !+ been propoe" to be+ m+ll + 16 mole$ule.71

!e +bo@e"e$ribe" tu"ie emp!+i<e t!e +"@+nt+'e o? n+notool to un"ert+n" t!eme$!+nim un"erlin' "n+mi$ e+rl e@ent o? protein el?+o$i+tion t!+t in@ol@e?orm+tion o? tr+nient oli'omeri$ pe$ie. A""ition+ll, in'lemole$ule met!o" +@oi"

































+@er+'in' o? in?orm+tion o@er t!e enemble, +""rein' u$! import+nt iue + t!e!etero'eneit o? t!e ?orme" pe$ie.

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&pecies (arrier

!e limite" +bilit to tr+nmit t!e in?e$tiou t+te bet4een prion protein o? "i??erentpe$ie i re?erre" to + pe$ie b+rrier. !e mole$ul+r b+i o? t!i pro$e i $urrentl poorl un"ertoo". Ho4e@er, it i !pot!ei<e" t!+t t!e pe$ie b+rrier i $ontrolle" bt!e mi?ol"in' o? t!e prion protein +n" it $on?orm+tion+l propertie.72,7% e@ert!ele, t!epe$ie b+rrier i belie@e" to be $loel rel+te" to t!e pe$i?i$it o? inter+$tion bet4eent!e templ+te +n" t!e ubtr+te.

Amon' ot!er ?+$tor, prim+r tru$ture (+mino +$i" eDuen$e) pl+ + $riti$+l role in"e?inin' t!e +bilit o? prion to prop+'+te t!rou'! + pe$ie b+rrier. t 'ener+ll !+ been

belie@e" t!+t t!e e??i$ien$ o? $rope$ie prion tr+nmiion i "ire$tl rel+te" to t!e"e'ree o? !omolo' in t!e prim+r eDuen$e o? prion ?or t4o pe$ie.7> *ome reportin"i$+te, !o4e@er, t!+t interpe$ie tr+nmiion i + mu$! more $ompleL p!enomenont!+n imple tr+nmiion bet4een $loel rel+te" pe$ie. #epen"in' on t!e pe$ie +n"t!e "ire$tion o? prion tr+nmiion, t!e pe$ie b+rrier o? prion in?e$tion @+riei'ni?i$+ntl. or eL+mple, ?ibrilli<+tion o? moue prion protein PrP (2%–1>>) $+n beee"e" 4it! ?ibril o? bot! moue prion +n" !+mter prion protein 4!i$! !+@e 9>U!omolo' in eDuen$e.7% En t!e ot!er !+n", t!e +''re'+tion o? !+mter prion protein$oul" onl be ee"e" b !+mter +mloi" ?ibril but not moue. em+r+bl, moue+mloi" ?ibril 4!i$! 4ere ee"e" b !+mter +mloi" ?ibril $oul" ee" ?ibrilli<+tion o?t!e !+mter monomer. Alter+tion o? p!enotpi$ p+ttern 4+ +lo ober@e" in t!e $ro

pe$ie re@ere tr+nmiion o? *up%5 protein o? S'##'ro(/#&% #&r&."%"'& I PSI [J to S+ p'r'0o*% or S+ -'/'n*% +n" b+$ to S+ #&r&."%"'&.75 A tron' @+ri+nt o? S+ #&r&."%"'& prion 4+ re@erible 4!en prop+'+te" @i+ + protein 4it! S+ p'r'0o*% prion "om+in, butt!e tr+nmiion @i+ S+ -'/'n*% prion "om+in +ltere" t!e p!enotpe o? iol+te" I PSI [J,reultin' in + 4e+er tr+in.75

Pre@iou tu"ie "emontr+te" t!+t + in'le +mino +$i" ubtitution 4it!in + !orteDuen$e tret$!, lo$+te" in + prion "om+in, "r+ti$+ll $!+n'e p+ttern o? $rope$ie prion [email protected]

A ne4 i"e+ !+ emer'e", u''etin' t!+t + prim+r tru$ture +lter t!e pe$trum o?

pre?erre" $on?orm+tion ?or + protein, t!ereb +??e$tin' tr+nmiion pe$i?i$it.%5 !er+n'e o? u$! pre?erre" $on?orm+tion mi'!t be eniti@e not onl to + prim+r eDuen$e but +lo to en@ironment+l $on"ition. t eem t!+t t!e eLiten$e o? prion tr+in +n"pe$ie b+rrier +re $loel rel+te" p!enomen+. A "itin$t tr+in $on?orm+tion o? *up%5!+ re$entl been i"enti?ie" t!+t i $+p+ble o? tr+nmiion ?rom S+ #&r&."%"'& to t!e!i'!l "i@er'ent C'n0"0' '!-"#'n%.%5 nteretin'l, t!e ne4l 'ener+te" prion tr+in $oul" be tr+nmitte" b+$ to e+t, timul+tin' +''re'+tion o? *up%5 in S+ #&r&."%"'&. !eereult u''et t!+t e@en tron' pe$ie b+rrier (onl >0U imil+rit in eDuen$e o?∼

























prion "om+in bet4een *$ +n" +) $+n be bri"'e" +n" t!ere?ore no pe$ie b+rrier $+n be$oni"ere" +bolute.%5

Gener+ll, t!e ee"in' pro$e i @ie4e" + prop+'+tion o? morp!olo' +n" t!e tru$tureo? pre?orme" ee". !i pro$e i belie@e" to o@er$ome eDuen$e +n"&or $on"ition

b+e" tru$tur+l pre?eren$e, reultin' in ?ibril t!+t in!erit t!e $!+r+$teriti$ o? t!etempl+te (re@ie4e" in re?. 7>). En + imil+r note, tr+nmiion t!rou'! + $rope$ie b+rrier i $oni"ere" to pro"u$e t!e +me tr+in o? t!e prion. Ho4e@er, tr+in 4it$!in'!+ been ober@e" ?or e@er+l prion tem. e$ent tu"ie illutr+te" t!+t +n +mloi"$+n +$$ommo"+te + i'ni?i$+nt $on?orm+tion+l 4it$! 4it!in + in'le ?ibril.%7 *u$! +$on?orm+tion+l 4it$! 4+ !o4n to o$$ur 4!en t!e +mino +$i" eDuen$e o? t!e pre$uror "i" not m+t$! t!e eDuen$e o? t!e templ+te. !e ?ibril ?orm+tion o? moue PrP4+ ee"e" 4it! pre?orme" ?ibril o? !+mter PrP. #epite t!e mim+t$! in +mino +$i"eDuen$e, in"i@i"u+l ?ibril 4ere +ble to re$ruit t!e !eterolo'ou re$ombin+nt prion protein. !e elon'+tion o? t!e ?ibril in t!i $+e pro$ee"e" t!rou'! +n +"+pt+tion o? +"i??erent $on?orm+tion+l t+te.%7

e$ent report +lo +"" to t!e $ompleLit o? t!e pe$ie b+rrier p!enomenon b !o4in't!+t t!e l+$ o? prion $o+''re'+tion ?or t4o pe$ie "oe not $orrel+te 4it! "e$re+e"$rope$ie prion tr+nmiion.76 !i ober@+tion, t!ere?ore, u''et t!+t priontr+nmiion pe$i?i$it i $ontrolle" +t t!e le@el o? $on?orm+tion+l tr+nition r+t!er t!+n$o+''re'+tion.

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*olecular *echanisms of Protein *isfolding

!ere i +n in$re+in' +mount o? e@i"en$e !o4in' t!+t m+n protein (i? not +ll) !+@et!e +bilit to ?orm ?ibril un"er +ppropri+te $on"ition.77,78 t eem t!+t +lt!ou'! t!e +re@er "i@ere in len't!, ?un$tion +n" lo$+tion in t!e or'+nim, +''re'+te +n" ?ibril !+@eimil+r morp!olo'ie +n" $ommon propertie. #epite t!e "i@erit o? tru$tur+l pe$uli+ritie o? +''re'+tion pre$uror, t!e m+ be ri$! in !eet, w!eli$e or e@enn+ti@el un?ol"e" protein; t!e +''re'+tion i +$$omp+nie" b "et+bili<+tion o? t!en+ti@e tru$ture +n" imult+neou ?orm+tion o? !eet. !eet +re ?orme" bet4een+ltern+tin' pepti"e tr+n" 4!i$! run perpen"i$ul+r to t!e lon' +Li o? t!e ?ibril(re@ie4e" in re?. 79). !ee tru$ture m+ be t+bili<e" eit!er b t!e net4or o? !"ro'en bon"in' bet4een bot! m+in$!+in +mi"e +n" b i"e $!+in rei"ue, 4!i$! turn t!eminto o$+lle" pol+r <ipper80 or b !"rop!obi$ inter+$tion.81 t !+ be$ome $ert+in

t!+t t!e +''re'+tion pro$e +n" !eet +$Duiition +re $on$erte" [email protected] !e+''re'+tion in"u$e" b t!e ?orm+tion o? !eetri$! tru$ture i + uni@er+l p!enomenon, not retri$te" to + pe$i+l $+te'or o? protein. !i u''et t!+t $ommonmole$ul+r me$!+nim mot liel un"erlie t!e +''re'+tion o? @+riou protein into!i'!l or"ere" ?ibrill+r +''re'+te.8% – 85

A$$or"in' to mole$ul+r "n+mi$ (M#) imul+tion, it !+ been u''ete" t!+t t!erel+ti@e t+bilit o? + monomerN bet+prone t+te "etermine t!e ?ibrillo'enei o? +



































pepti"e.86 n$re+in' rel+ti@e t+bilit o? bet+prone t+te reult in $!+n'in' t!e+''re'+tion p+ttern ?orm "ior"ere" +''re'+tion to ?ibril ?orm+tion, 4it! onp+t!4+interme"i+te +n" ?in+ll to ?ibrillo'enei 4it!out +n interme"i+te.

Atomi$ ?or$e mi$ro$op (AM) 4+ +lo intrument+l in elu$i"+tin' t!e mole$ul+r

ori'in o? ?ibril propertie b pro@i"in' ini'!t into 4!+t "etermine u$! m+teri+l + +n+mloi" ?ibril.87 *e@er+l pepti"e 4!i$! re+"il ?orm +mloi" ?ibril 4it! lo4 eDuen$eimil+rit 4ere +n+l<e" in term o? ben"in' ri'i"it o? t!e ?orme" ?ibril. !eme$!+ni$+l propertie o? ?ibrill+r tru$ture 4ere $!+r+$teri<e" b AM topo'r+p!i$ "+t+4!i$! en+ble" t!e +n+li o? t!e "e$+ o? t+n'ent +lon' t!e ?ibril. *u$! "e$+ +$$ur+telre?le$t t!e me$!+ni$+l propertie o? t!e ?ibril]ome o? 4!i$! +ppe+r to be ?leLible +n"ome +re @er ti??. /en"in' ri'i"itie ?or "i??erent ?ibril @+r b + mu$! + > or"er o?m+'nitu"e. t 4+ !o4n t!+t t!e m+or $ontribution to t!e ?ibrilN ri'i"it $ome ?rom t!e'eneri$ !"ro'enbon"in' net4or o? b+$boneb+$bone inter+$tion, 4!i$! imo"ul+te" b i"e$!+in inter+$tion.87 !e +bo@e"e$ribe" ?in"in' onl rein?or$e t!e!pot!ei t!+t t!e +bilit to ?orm +mloi" ?ibril i + 'eneri$ propert be$+ue t!ee

tru$ture +re t+bili<e" b m+in$!+in inter+$tion o? t!e polpepti"e b+$bone. t +loeLpl+in 4! o m+n unrel+te" protein ?orm u$! ?ibrill+r +''re'+te.7>

t i be$omin' $le+r t!+t $urrentl +@+il+ble 4i"el ue" enembleb+e" met!o" be+rlimit+tion t!+t pre@ent ?ull $!+r+$teri<+tion +n" un"ert+n"in' o? protein mi?ol"in' +n"+''re'+tion p!enomen+. *u$! met!o" pro@i"e + 'ener+l pi$ture o? + tem in 4!i$! t!ein?orm+tion i +@er+'e" o@er t!e enemble o? +ll $on?orm+tion preent in t!e tem.Ho4e@er, mi?ol"in' +n" e+rl e@ent in protein +''re'+tion +re too Dui$ +n" in@ol@epe$ie t!+t +re too m+ll ?or eLperiment+l probin' b mot $urrentl +@+il+blete$!niDue. !e limit+tion o? t!e $urrent met!o" ?or$e $ientit to loo ?or +ltern+ti@etool to tu" me$!+nim o? mi?ol"in' +n" +''re'+tion. Gi@en t!e in!erent n+no$+le

o? t!ee in'lemole$ule e@ent, it i ine@it+ble t!+t eLitin' +n" emer'in' n+noim+'in'tool 4ill be +pplie" to ol@e t!ee $!+llen'in' problem b openin' ne4 poibilitie toun"ert+n" t!e me$!+nim o? protein "ie+e, to impro@e "i+'noi +n" to "e@elope??e$ti@e t!er+peuti$ +ppro+$!e. urrent tren" +n" +"@+n$e in n+no$ien$e in"i$+tet!+t in'lemole$ule met!o" mi'!t !elp to o@er$ome t!e limit+tion o? $urrentl ue"met!o".

or eL+mple, re$ent tu"ie uin' in'lemole$ule ?luore$en$e reon+n$e ener' tr+n?er (*M) +n" ?luore$en$e $orrel+tion pe$tro$op in@eti'+te" t!e tru$ture +n""n+mi$ o? monomeri$ prion e+t protein *up%5.88 !e reult o? t!i tu""emontr+te" t!+t t!e M p+rt (termin+l +n" Mi""le p+rt) o? t!e monomeri$ protein+$$ommo"+te +n enemble o? $on?orm+tion in p!iolo'i$+l bu??er. !e enemble$onit o? r+pi"l inter$on@ertin' $omp+$t $on?orm+tion in"i$+tin' t!e !i'!l "n+mi$n+ture o? protein $on?orm+tion+l p+$e.

!i tu" rein?or$e" t!e i"e+ t!+t ne4 eLperiment+l tool +re reDuire" to ?ull$!+r+$teri<e protein mi?ol"in' +n" +''re'+tion +t t!e le@el o? in'le mole$ule. *u$!tool 4ill +llo4 un+mbi'uou me+urement o? t!e ineti$ o? inter$on@erion bet4een"i??erent protein $on?orm+tion +n" "itin'ui! $on?orm+tion+l $!+n'e in in"i@i"u+l

















protein mole$ule prior to +''re'+tion + 4ell + $!+n'e in"u$e" b inter+$tion o? protein 4it! +not!er protein or ot!er ?+$tor. t i +lo import+nt to note t!+t ome$on?orm+tion (mi?ol"e" t+te) mi'!t be more import+nt in +''re'+tion p+t!4+ t!+not!er e@en t!ou'! t!e +re onl tr+nientl popul+te". !e tr+nient n+ture o? mi?ol"e"$on?orm+tion m+e t!em not +men+ble to tr+"ition+l met!o". e4 tool +re emer'in'

4!i$! +re $+p+ble o? +""rein' t!e mi?ol"in' p!enomenon +t t!e le@el o? + in'lemole$ule.

!e tr+nient n+ture o? mi?ol"e" $on?orm+tion +n" el?prop+'+tin' n+ture o? +mloi"!i'!li'!t t!e import+n$e o? un"ert+n"in' 4!+t inter+$tion bet4een protein mole$ule"ri@e t!e ?orm+tion o? + t+ble nu$leu o? +''re'+tion. Mi?ol"e" +''re'+tionprone$on?orm+tion o? + protein mole$ule "i??er ?rom ot!er $on?orm+tion b t!eir en!+n$e" propenit to +o$i+te 4it! e+$! ot!er, promotin' ?orm+tion o? n+no+''re'+te.89 Amonomeri$ protein !oul" un"er'o tru$tur+l reor'+ni<+tion to +"opt +n interme"i+te$on?orm+tion+l t+te reDuire" ?or t!e initi+tion o? +''re'+tion.90 !e propenit ?or u$!+"+pt+tion $oul" be mo"ul+te" b + prim+r eDuen$e or eLtern+l ?+$tor u$! +

en@ironment+l $on"ition, inter+$tion 4it! ot!er protein, toLin, $ellul+r $omponent+n"&or $ellul+r membr+ne.

e$entl, +tomi$ ?or$e pe$tro$op in'lemole$ule un?ol"in' met!o"olo' !+ been+pplie" to tu" t!e +mloi"o'eni$ propertie o? 2mi$ro'lobulin91 +n" t!e$on?orm+tion+l "i@erit o? +lp!+nu$lein]+ protein in@ol@e" in P+rinonN "ie+e.92 A in'leprotein mole$ule 4+ ?l+ne" b t!ree 27 "om+in, 4!i$! +$te" + mole$ul+r!+n"le + 4ell + + 4elli"enti?i+ble ?in'erprint in t!e me+ure" ?or$e $ur@e +llo4in'$le+r re$o'nition o? i'n+l ?rom me$!+ni$+l tret$!in' o? in'le +lp!+nu$leinmole$ule. *u$! +n +ppro+$! probe t!e ?ull $on?orm+tion+l p+$e o? t!e protein,i"enti?in' e@en poorl popul+te" $on?ormer o? +lp!+nu$lein. !ree m+in "itin$t

$on?orm+tion 4ere i"enti?ie" +n" $l+i?ie" + r+n"om $oil, me$!+ni$+ll 4e+ +n" bet+lie tru$ture. !e l+tter +re "ire$tl rel+te" to +''re'+tion o? +lp!+nu$lein.92 nteretin'l, p+t!olo'i$+l $on"ition 4!i$! +re no4n to in$re+e propenit o? +lp!+nu$lein to +''re'+te, u$! + !i'! ioni$ tren't! +n" preen$e o? u2[, !i?te"$on?orm+tion+l eDuilibrium to4+r" bet+lie tru$ture. Alo, t!i +ppro+$! 4+ ue" to$!+r+$teri<e p+t!olo'i$+l mut+nt o? +lp!+nu$lein]A%0P, A5% +n" >6.9% !etu" re@e+le" i'ni?i$+nt "i??eren$e in t!e $on?orm+tion+l be!+@ior o? t!e mut+nt$omp+re" to t!e 4il"tpe protein. All mut+nt !+" !i'!er popul+tion o? bet+lietru$ture, in"i$+tin' t!eir !i'!er propenit to +''re'+te.9%

!e +bo@e"e$ribe" tu"ie rein?or$e" t!e !pot!ei propoe" e+rlier t!+t mi?ol"e"$on?orm+tion 4!i$! +re $+p+ble o? tri''erin' protein +''re'+tion +re $!+r+$teri<e" bele@+te" propenit to inter+$t 4it! one +not!er.9> !e ue o? AM ?or$e pe$tro$op !+ been propoe" to probe t!e propertie o? inter+$tin' in"i@i"u+l mole$ule o? t!e+''re'+tin' protein.9>,95 !e tr+te' ?or u$! $!+r+$teri<+tion i "e$ribe" in "et+ilele4!ere.89,96,97 /rie?l, in"i@i"u+l mole$ule +re $o@+lentl +tt+$!e" to AM tip +n" t!e probe" ur?+$e uin' re$entl "e@elope" ur?+$e $!emitr.89 !e "imer $+n ?orm 4!ent!e tip +ppro+$!e t!e ubtr+te +n" t!e inter+$tin' ?or$e bet4een mole$ule 4it!in"imeri$ $ont+$t +re me+ure" upon tip retr+$tion. M$Alliter et +l.9> !+@e ue" AM to





































tu" mi?ol"in', in"u$in' inter+$tion in t!ree "i??erent +n" tru$tur+ll "itin$ti@e protein: wnu$lein, +mloi" pepti"e (A) +n" lo<me. !e tren't! o? interproteininter+$tion 4+ me+ure" +t @+riou pH @+lue, uin' pH + + timul+tin' ?+$tor ?or$on?orm+tion+l $!+n'e in t!e protein. 3o4 pH @+lue +re no4n to in"u$e mi?ol"in'o? t!ee protein promotin' +''re'+tion +n" imult+neoul $on?orm+tion+l tr+nition to

tpe tru$ture.98

!e propenit o? + protein ?or +''re'+tion, it +$Duiition o? !eet$on?orm+tion +n" tren't! o? interprotein inter+$tion 4ere ?oun" to $orrel+te @er 4ell,u''etin' intim+te rel+tion!ip +mon' +ll t!ree.9> !e reult o? t!i tu" illutr+te t!e po4er o? ?or$e pe$tro$op in +""rein' mole$ul+r me$!+nim o? protein mi?ol"in'+n" +''re'+tion b me+urin' t!e tren't! o? interprotein inter+$tion.89,9> A re$ent+ppli$+tion o? t!i in'lemole$ule +ppro+$! to +lp!+ nu$lein97 le" to + ?in"in' t!+t t!e?orm+tion o? + "imer o? mi?ol"e" +lp!+nu$lein "r+m+ti$+ll in$re+e t!e li?etime o?t!e protein mi?ol"e" t+te. *u$! t+bili<+tion o? mi?ol"e" protein in + "imeri$ ?ormenormoul in$re+e t!e propenit to +''re'+te ?urt!er. !i i + ?un"+ment+l ?in"in'u''etin' t!+t "imeri<+tion o? +mloi"o'eni$ protein tri''er t!e ?orm+tion o? t!e"ie+eprone +emblie +n" t!u initi+tin' t!e "ie+e.

e !+@e ue" t!i po4er?ul ?or$e pe$tro$op +ppro+$! to +n+l<e inter+$tion bet4eenin"i@i"u+l mole$ule o? t!e !ort pepti"e GOOY 4it! + $teine in$orpor+te" to?+$ilit+te immobili<+tion o? t!e pepti"e ?or t!e ?or$e pe$tro$op tu"ie. !i pepti"e i+ p+rt o? *up%5 e+t prion protein +n" 4+ ?oun" to be +mloi"o'eni$, ee"in'+''re'+tion o? t!e entire protein.99 !e +''re'+tion o? t!i pepti"e reult in +''re'+te o? ?ibrill+r morp!olo' in + 4i"e r+n'e o? en@ironment+l $on"ition. !e +''re'+tionineti$ ?or t!i pepti"e 4+ ober@e" to be t!e ?+tet +t pH 5.6 +mon' +ll tete" pH@+lue.100 e !+@e $!oen pH F 5.6 to me+ure t!e inter+$tion bet4een in"i@i"u+l pepti"e. !e pepti"e monomer 4ere $o@+lentl +tt+$!e" to AM tip +n" mi$+ ur?+$euin' termin+l $teine rei"ue 4it! ur?+$e $!emitr pre@ioul "e@elope" +n" tete".89

Me+urement o? rupture ?or$e o@er + r+n'e o? lo+"in' r+te reulte" in + "n+mi$ ?or$epe$trum (#*). 3igure ;A !o4 t!e #* plot obt+ine" ?or inter+$tion bet4eenGOOY pepti"e +t pH 5.6. !e plot !+ @er "itin$t p+rt 4!i$! "i@i"e #* intoe@er+l lope. #io$i+tion o? intermole$ul+r $ont+$t t!+t in@ol@e o@er$omin' moret!+n one +$ti@+tion b+rrier reult in + "n+mi$ ?or$e pe$trum 4it! e@er+l"itin'ui!+ble line+r re'ime $!+r+$teri<e" b "i??erent lope.101 ? t!e "n+mi$ ?or$epe$trum i "i@i"e" into t4o p+rt, +umin' t4o line+r re'ime in t!e r+n'e o? lo+"in'r+te bet4een 200 +n" 120,000 p&e$, t!ee t4o lope o? #* plot ?or t!e pepti"e pepti"e "imeri$ $ont+$t +re tr+nl+te" into t4o +$ti@+tion ener' b+rrier. A @er teepline+r plot $!+r+$teri<e t!e rupture ?or$e "epen"en$e +t !i'! lo+"in' r+te. !i lope pro"u$e t!e o??r+te "io$i+tion $ont+nt + !i'! + 1>7 1 4!en ?itte" 4it! /ellNmo"el.101 !e e$on" re'ime +t lo4 lo+"in' r+te i $!+r+$teri<e" b + mu$! m+ller@+lue o? o??r+te $ont+nt, o?? F 1.8 1. !e "imer li?etime $orrepon"in' to t!i @+lue o?o?? r+te $ont+nt 4+ ?oun" to be 0.6 e$on", u''etin' !i'! t+bilit o? "imeri$ pe$ie$omp+re" to t!e "n+mi$ $!+r+$teriti$ o? t!e protein in monomeri$ t+te.100 !e "imer,t!u, m+ er@e + t+ble nu$lei ?or t!e ?orm+tion o? multimeri$ +n" +''re'+te" ?orm o?t!e pepti"e. !i ober@+tion i in line 4it! + pre@iou tu" t!+t u''ete" + $riti$+l roleo? "imeri<+tion in t!e +''re'+tion o? +nu$lein.97 Moreo@er, + imil+r p+ttern 4+ober@e" ?or A>0 pepti"e.100 !u, +ll "+t+ le+" to + ne4 mo"el o? t!e protein





































+''re'+tion in 4!i$! t!e @er ?irt t+'e, t!e ?orm+tion o? "imer, i + e tep tri''erin't!e entire el?+embl pro$e.

i'ure %#n+mi$ ?or$e pe$trum o? GOOY pepti"e inter+$tion me+ure" +t pH 5.6.

n $on$luion, 4e belie@e t!+t ?urt!er eLploit+tion o? in'lemole$ule +ppro+$!e 4ill pro@i"e ne4 import+nt ini'!t into t!e me$!+nim o? protein mi?ol"in' +n"+''re'+tion. e +nti$ip+te t!+t in'lemole$ule met!o" 4ill +"@+n$e our un"ert+n"in'o? u$! p!enomen+ + mi?ol"in', +''re'+tion +n" n+ture o? toLi$ pe$ie. *u$!no4le"'e i $riti$+l ?or $ontrollin' t!ee pro$ee +n" t!e "e@elopment o? e??e$ti@et!er+peuti$ +'ent to pre@ent rel+te" neuro"e'ener+ti@e "ie+e.

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Acknowledgements

!e +ut!or t!+n 3u"+ *. *!l+!teno ?or !er !elp 4it! AM im+'in'.

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3ootnotes

Pre@ioul publi!e" online: 444.l+n"ebio$ien$e.$om&ourn+l&prion&+rti$le&1%125

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3inancial &upport

!e 4or 4+ upporte" b t!e ?ollo4in' 'r+nt: #E (#G02086>579) +n" AE (/..*P 98%20>) (+ll to Y.3.3.).

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http://www.landesbioscience.com/journals/prion/article/13125








http://www.landesbioscience.com/journals/prion/article/13125






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