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Stem-cell therapy has moved one stepcloser to reality, with the findingthat human neural stem cells canrepair stroke-induced damage inrat brains.

Gary Steinberg (Stanford Univer-sity, California, USA) and colleagueshave shown that transplanted fetalcells can home in on damaged brainregions and form replacement neuralcells (Proc Natl Acad Sci USA 2004,101: 11839–44). “We’re not saying wecan treat patients immediately, but it’sa big step forwards”, he says.

The team isolated neural stem cellsfrom 16–20-week-old human fetusesthen swelled their numbers byculturing them as clusters—orneurospheres—with a cocktail of threedifferent growth factors. A week aftersurgically inducing a stroke in rats,they injected a total of 300 000 cells atthree locations in the rats’ brains, each

just a few millimetres away from thestroke-induced lesion.

4 weeks later, around a third of thetransplanted cells were still alive.About half of these expressed theimmature neuronal marker � tubulinIII, indicating that these cells wereturning into neurons. The remainderwere still in their stem-cell form, orhad become GFAP-positive astrocytes.

Transplant-derived neurons weremore likely to be found close the lesionedge, having travelled up to 1·2 mm toreach their destination. Newly formedastrocytes were found slightly furtheraway from the lesion. Steinberg thinksthat the damaged cells act as a distresscall beckoning the transplanted cells intheir direction. Other signals may theninstruct the new arrivals to turn intoneurons or astrocytes.

But Steinberg is not the first toshow that transplanted human neural

stem cells can replace missing neurons,says Evan Snyder (The BurnhamInstitute, La Jolla, California, USA).And the next step would be to showrecovery of behaviour.

Steinberg thinks that fetal neuralstem cells will have importantadvantages over their adult andembryonic rivals. Adult neural stemcells show poor survival and migrationafter transplantation, he says. And theuse of human embryonic stem cells ishampered by ethical concerns and, inthe USA, federal restrictions hampertheir availability as a research tool.

“[But human foetal] neurosphereswill probably not be the way to go,”cautions Snyder. “We probably needmore stable and predictable cell lines.”Researchers could add to genes tomaintain the cells’ genetic stability andboost their growth in culture.Helen Agoston

Stem cells show promise as stroke therapy

Researchers from the USA havediscovered how wild-type � synuclein isdegraded, and describe that mutantforms could build up in Parkinson’sdisease (PD) by blocking their ownbreakdown (Science 2004; 305: 1292–95).

The physiological functions ofnormal � synuclein are largelyunknown, and until now it was amystery how the protein was degraded.In PD, however, aberrant forms of� synuclein accumulate in neurons asLewy bodies—“although the reason forthat was also unknown”, explains studyleader Ana Maria Cuervo (AlbertEinstein College of Medicine, NewYork). “Our work shows thisaccumulation occurs through theescape of these mutant proteins fromthe lysosome systems that normallyeliminate them.”

Cuervo’s team noticed that normal� synuclein has a pentapeptide motifthat might encourage its breakdown viaa type of lysosomal degradation knownas chaperone mediated autophagy(CMA). Experiments in PC12 cellsshowed that � synuclein did bind to thespecialised hsc70 chaperone molecule inthe cytosol, and that the complex

produced then bound to a receptorknown as lamp2a on the lysosomal

membrane. The � synuclein was theninternalised and broken down byhydrolytic enzymes. In the presence ofammonium chloride, a lysosomalinhibitor, the process came to a halt.

When the same experiments weredone with the PD-associated A30P andA53T mutant forms of the protein,complexes with the chaperone moleculeformed again. However, when thesebound to the lamp2a receptor, nointernalisation occurred. This bindingwas so persistent that it prevented anymore of the mutant forms—or otherproteins—from binding. “Not only

were the mutant synucleins notremoved from the cell, but because thelysosomes were blocked by theseproteins, other abnormal or damagedcomponents could not be broken downeither, resulting in a cell log-jam andeventually death”, explains Cuervo.

The research has implicationsbeyond PD. Failures in new lysosomalsystems such as CMA may be involvedin other neurological diseases such asAlzheimer’s and Huntington’s diseases,perhaps even cancer. “We nowunderstand one of the earliest events inPD”, says Cuervo. “This informationcould help us design treatments aimedat restoring CMA.”

Randolph Nixon of New YorkUniversity remarked: “These studiesreveal new facets of an increasinglyappreciated close relationship betweenlysosomal system dysfunction andneurodegeneration, which are likelyto be broadly relevant to pathogenesisin ageing-related neurodegenerativedisease. The findings should sparkdetailed investigations on the functionalconsequences of impaired CMA andmacroautophagy in neurons.”Adrian Burton

Parkinson’s disease: �-synuclein build-up explained

Neurology Vol 3 October 2004 http://neurology.thelancet.com

� synuclein forms Lewy bodies in PD

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