Oxidative Stress and Genetics in the Pathogenesis of Parkinson's Disease

J

Neurobiology of Disease 7, 240–250 (2000)

doi:10.1006/nbdi.2000.0319, available online at http://www.idealibrary.com on

REVIEW

Oxidative Stress and Genetics in thePathogenesis of Parkinson’s Disease

Yi Zhang,* Valina L. Dawson,* ,†,‡ and Ted M. Dawson* ,†

†Department of Neurology, *Department of Neuroscience, and ‡Department of Physiology,ohns Hopkins University School of Medicine, Baltimore, Maryland 21287

Received June 29, 2000; accepted for publication July 5, 2000

Parkinson’s Disease (PD) is the second most common chronic neurodegenerative disease charac-terized by the progressive loss of dopamine neurons, leading to rigidity, slowness of movement, resttremor, gait disturbances, and imbalance. Although there is effective symptomatic treatment for PD,there is no proven preventative or regenerative therapy. The etiology of this disorder remains un-known. Recent genetic studies have identified mutations in a-synuclein as a rare cause of autosomaldominant familial PD and mutations in parkin as a cause of autosomal recessive familial PD. The morecommon sporadic form of PD is thought to be due to oxidative stress and derangements in mito-chondrial complex I activity. Understanding the mechanism by which familial linked mutations andoxidative stress cause PD has tremendous potential for unraveling the mechanisms of dopamine celldeath in PD. In this article, we review recent advances in the understanding of the role of genetics andoxidative stress in the pathogenesis of PD. © 2000 Academic Press

Key Words: Parkinson’s disease; neurodegeneration; a-synuclein; parkin; substantia nigra pars
compacta; dopamine; reactive oxygen species.
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INTRODUCTION

Parkinson’s Disease (PD) is a relatively commonneurodegenerative disorder affecting 1% of thepopulation above the age of 65 (Lang and Lozano,1998a, b). The clinical manifestations of PD include,bradykinesia, rest tremor, rigidity, gait abnormalities,and postural instability. The initial description ofPD was based on six cases reported by Parkinson(1817). Over the last 180 years the etiology of thedisease still remains unknown. PD is character-ized pathologically by a selective loss of dopaminer-gic neurons in the substantia nigra pars compacta(SNC) leading to a loss of dopamine, its metabo-lites including homovanillic acid (HVA), 3,4-dihy-droxyphenylacetate (DOPAC), its biosynthetic en-zyme, tyrosine hydroxylase (TH), and the dopaminetransporter (DAT) in the striatum, as well as in theSNC (Dunnett and Bjorklund, 1999; Jenner and Ola-
now, 1998). These findings are consistent with re-
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duced dopamine markers in positive emission tomog-raphy (PET) imaging studies in PD patients, and inasymptomatic individuals at risk for developing PD(Burn et al., 1992; Holthoff et al., 1994; Marek et al.,1996; Piccini et al., 1997; Sawle et al., 1992; Seibyl et al.,998). In PD, dopaminergic ventral tegmental areaVTA) neurons and noradrenergic neurons of the lo-us coeruleus (LC) are also affected. Neuronal degen-ration in PD also affects pigmented and nonpig-ented neurons outside the substantia nigra and the

rainstem and can involve multiple neurotransmitterystems. Important neuronal loss and Lewy bodies,he pathologic hallmark of PD, have been reported inerebral cortex, anterior thalamus, hypothalamus,mygdala and basal forebrain. Classical Lewy bodiesre neuronal proteinaceous cytoplasmic inclusionsith a dense eosinophilic core surrounded by a clear

alo and are usually present in the SNC and LC of PDatients (Galloway et al., 1992; Galvin et al., 1999a;

Pollanen et al., 1993).

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OXIDATIVE STRESS AND PD

Although the pathology underlying PD is clear, it isstill not known why SNC DA neurons die. A variety ofmarkers and indices in PD patients and animal modelsindicate involvement of oxygen-free radicals and oxi-dative stress in the pathogenesis of PD. These includelipid peroxidation (Dexter et al., 1986, 1989; Jenner,1996; Smith et al., 1987), reduced glutathione (Sian etal., 1994), increased levels of iron and reduction offerritin concentrations in the SNC of PD (Dexter et al.,1990, 1992; Jellinger et al., 1993). Faults with the respi-ratory chain and dopamine metabolism have also beentheorized to contribute to free radical production (Jen-ner, 1996). A variety of additional pathogenic mecha-nisms have been proposed including exogenous orendogenous toxins, including dopamine and its me-tabolites; free-radical-mediated oxidative injury; mito-chondrial abnormalities; perturbations of the neuronalcytoskeleton/axonal transport; excitotoxicity; calci-um-induced injury and the role for iron, copper, zinc,and programmed cell death (Dunnett and Bjorklund,1999; Jenner and Olanow, 1998).

The discovery that a synthetic heroin analog,1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine(MPTP) can selectively damage neurons in the nigro-striatal dopaminergic pathway and produce parkin-sonism in humans, nonhuman primates, and mice hasprovided a valuable model for investigating mecha-nisms of selective sensitivity of DA neurons (Kopinand Markey, 1988; Langston, 1996). Accidental use ofMPTP by heroin addicts led to the discovery thatMPTP caused parkinsonism in humans. In humansand nonhuman primates, MPTP induces irreversibleand severe motor abnormalities that are indistinguish-able from those in PD. In monkeys and mice, MPTPexposure induces many of the biochemical and neu-ropathological changes in the nigrostriatal dopaminer-gic pathway that are observed in postmortem studiesof PD patients (Table 1). These changes include amarked reduction in striatal DA content and metabo-lites, as well as a significant reduction in the numberof DA cell bodies in the SNC. Additionally, in mon-keys MPTP induces the formation of intraneuronaleosinophilic inclusions which resemble Lewy bodies(Forno et al., 1993). Although MPTP produces an acuteintoxication, it is one of the best animal models for thestudy of PD. Another model which is widely used isthe 6-hydroxydopamine (6-OHDA) model (Dunnettand Bjorklund, 1999; Jenner and Olanow, 1998). As
animal models of the familial-linked genes that cause
PD in humans are developed (see below) these modelswill replace the MPTP intoxication model as the modelof choice.

Since the original discovery of MPTP, a number ofinvestigations have provided important clues to un-derstanding the mechanisms of selective DA neuronalloss in response to MPTP and these investigationshave also provided important clues to understandingthe etiology and pathogenesis of sporadic PD. In thecentral nervous system MPTP is oxidized to MPP1 bymonoamine oxidase B (MAOB) (Heikkila et al., 1984;Trevor et al., 1987). MPP1 is taken up by dopamine

eurons via the high affinity dopamine transporterJavitch et al., 1985). MPP1 is then actively transportednto mitochondria where it can interfere with mito-hondrial respiration through inhibition of complex Iesulting in increased formation of the superoxidenion (Hasegawa et al., 1990). Przedborski and col-eagues (Przedborski et al., 1992) reported that trans-

genic mice which overexpress the cystolic copper/zinccontaining superoxide dismutase (SOD-1) were moreresistant to MPTP-induced dopaminergic neurotoxic-ity then wild-type mice. These in vivo experimentsimplicate the superoxide anion in MPTP neurotoxicityhowever, superoxide is a poorly reactive radicalwhich in and of itself is not very toxic. Most of thetoxicity observed following superoxide anion genera-tion is believed to be due to the reaction of the super-oxide anion with other reactive oxygen species such asnitric oxide (NO) (Beckman, 1994). Reaction of thesuperoxide anion with NO produces the potent oxi-dant peroxynitrite, which has been implicated in anumber of neurotoxic and neurologic disease models(Crow and Beckman, 1995) (Fig. 1). Consistent withthis notion is the observation that relatively selective

TABLE 1

MPTP-Induced Parkinsonism

Idiopathic PD MPTP Intoxication

Bradykinesia BradykinesiaRigidity RigidityPostural instability Postural instabilityRest tremor Rest tremorLoss of DA, TH, DAT Loss of DA, TH, DATResponse to l-DOPA Response to l-DOPALewy bodies

(a-synuclein andubiquitin positive)

Lewy body-like inclusions(a-synuclein andubiquitin positive)

ecrements in complex I Decrements in complex I

neuronal NO synthase (nNOS) inhibitors are neuro-

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protective against MPTP-induced neurotoxicity andmutant mice which lack the nNOS gene (nNOS2/2) aresignificantly more resistant to MPTP-induced neuro-toxicity when compared with wild-type littermatecontrols (Grunewald and Beal, 1999; Matthews et al.,1997; Przedborski et al., 1996; Schulz et al., 1995).

In addition to the role of nNOS-derived NO inMPTP pathogenesis recent studies suggest that iNOS-derived NO may play a prominent role in the degen-eration of dopaminergic neurons in the MPTP model(Dehmer et al., 2000; Liberatore et al., 1999). Gliosis is asalient neuropathologic feature in the SNC and stria-tum in the MPTP mice model (Dehmer et al., 2000;Liberatore et al., 1999). SNC and striatal gliosis is also

prominent feature of sporadic PD (Schneider andenaro, 1988). Furthermore, postmortem analysis ofumans with MPTP-induced parkinsonism demon-trates active gliosis, suggesting that reactive glia mayontribute to the chronic degeneration of DA neuronsForno et al., 1992; Langston et al., 1999). Accompany-

ing the gliosis is the appearance of activated microglialcells that express inducible NO synthase (iNOS). As-

FIG. 1. Model of MPTP-induced dopaminergic cell death. MPP1,the active metabolite of MPTP, is concentrated in DA neurons viathehigh affinity dopamine transporter. MPP1 is then concentrated inmitochondrial where it ihnibits complex 1, which leads to superox-ide anion (O2

•2) formation. The superoxide anion reacts with nitricxide (NO) which is produced by both neuronal NOS (nNOS) and

nducible NOS (iNOS) to form peroxynitrite (ONOO2), which dam-ages intracellular proteins and DNA to cause cell death. DNAdamage activates the poly (ADP-ribose) polymerase (PARP), whichdepletes cells of energy stores through decrements in NAD andATP. This coupled with mitochondrial poisoning leads to cell death.This model may have direct relevance to idiopathic PD as postmor-tem analysis reveals increases in nitrotyrosine, a marker of ONOO2

mediated damage, and induction of iNOS.

sociated with the increase in iNOS immunoreactivity

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are increases in iNOS catalytic activity and increasesin nitrotyrosine levels in both striatum and ventralmidbrain following MPTP intoxication. Approxi-mately twice as many neurons are spared from thetoxic effects of MPTP in mice lacking the gene foriNOS (iNOS2/2) compared to their saline-injectedwild-type littermates implicating iNOS derived NO inthe cell death of DA neurons following MPTP intoxi-cation. Interestingly, dopaminergic fibers and levels ofdopamine and metabolites in the striatum were notspared from the toxic effects of MPTP in iNOS2/2 mice(Dehmer et al., 2000; Itzhak et al., 1999; Liberatore et al.,999), which differs from that observed in nNOS2/2

mice in which DA and its metabolites are spared fromthe toxic effects of MPTP (Liberatore et al., 1999; Pr-zedborski et al., 2000). Thus, MPTP elicits its neuro-toxic effects by iNOS-derived NO acting predomi-nantly on DA neurons in the SNC and nNOS-derivedNO damaging primarily dopaminergic fibers and ter-minals in the striatum (Fig. 2). Thus, future therapy forParkinson’s Disease may require agents which inhibitthe degenerative effects of iNOS in the substantianigra pars compacta and agents which prevent dopa-minergic terminal degeneration or promote their sur-vival within the striatum. These observations in themouse MPTP model of parkinsonism may have directrelevance to sporadic PD as NOS inhibitors preventthe toxic effects of MPTP in nonhuman primates(Hantraye et al., 1996) and markers of NO formation,including nitrotyrosine immunoreactivity and iNOSimmunoreactivity have been observed in the SNC ofPD patients (Good et al., 1998).

FIG. 2. nNOS and iNOS contribute to MPTP-induced dopaminer-gic cell death. nNOS-derived NO contributes to the degeneration ofDA terminals and secondary loss of DA cell bodies. iNOS reactivemicroglia directly contribute to the degeneration of DA cell bodies.
See text for Discussion.

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Although evidence is accumulating that both neu-ronally and microglial derived NO may contribute tothe pathogenesis of MPTP-induced dopaminergic celldeath through interactions with the superoxide anionto form peroxynitrite, the downstream targets of per-oxynitrite are poorly understood. MPTP-induced do-paminergic damage can be prevented by inhibitingMAOB, DA uptake, and blocking N-methyl-d-aspar-tate (NMDA) glutamate receptors (Dunnett and Bjork-lund, 1999; Jenner and Olanow, 1998), and the toxiceffects can also be prevented by overexpressing anti-oxidant enzymes such as SOD-1 (Przedborski et al.,1992), manganese SOD (SOD-2) (Klivenyi et al., 1998),as well as the overexpression of dominant negativeagainst interleukin-1 converting enzyme (Klevenyi etal., 1999). Mice lacking glutathione peroxidase aremore vulnerable to MPTP toxicity (Klivenyi et al.,2000). All these studies point to a prominent role ofreactive oxygen species in the cell death that occursfollowing MPTP administration. Recent investigationssuggest that reactive oxygen species mediated damageof DNA can activate poly (ADP-ribose) polymerase(PARP), a DNA repair enzyme (Berger, 1985; Szaboand Dawson, 1998). PARP ADP-ribosylates a varietyof nuclear proteins including PARP itself, histones,topoisomerases, and other proteins involved in DNArepair process (de Murcia and Menissier de Murcia,1994; Lautier et al., 1993). The ADP-ribosylation ofthese proteins by PARP consumes NAD and energy,which in the setting of mitochondrial respiration poi-soning leads to severe decrements in energy and sub-sequent cell death (Berger, 1985; Szabo and Dawson,1998). A role for PARP activation in MPTP-inducedDA cell death is supported by studies in which phar-macologic inhibitors of PARP prevent DA injury fol-lowing MPTP (Cosi et al., 1996) and the observationthat PARP selectively ADP-ribosylates a unique set ofproteins in the substantia nigra dopaminergic contain-ing neurons following MPTP administration (Mandiret al., 1999). Furthermore, dopaminergic neurons frommutant mice lacking PARP are dramatically sparedfrom the toxic effects of MPTP (Mandir et al., 1999)Fig. 1).

The prominent role of oxidative stress in dopami-ergic cell death following MPTP intoxication mayave direct relevance to the pathogenesis of PD. MPTP

s a potent complex 1 inhibitor, and most of MPTP’soxic actions are thought to directly stem from thenitial inhibition of complex 1 (Dunnett and Bjorklund,999; Jenner and Olanow, 1998). This leads to theeneration of mitochondrial-derived reactive oxygen
pecies, which then set in motion the deleterious cas-
ade of dopaminergic cell death. Despite the fact thatPTP has led to tremendous insights into the mech-

nism by which dopamine cells die and the fact that itimics many of the features of PD, it is an acute

ntoxication model which differs dramatically fromhe chronic neurodegenerative process of PD. The

ost striking difference between MPTP intoxicationnd PD is the lack of significant Lewy body formationollowing MPTP administration. This probably relateso the use of MPTP as an acute intoxication model. It

ould be important to determine whether chronic lowevel inhibition of complex I would lead to selectiveegeneration of dopaminergic cell bodies and termi-als with the concomitant formation of eosinophilic

ntracytoplasmic inclusions, which stain for ubiquitinnd a-synuclein, markers enriched in Lewy bodies

(see below). Interestingly, MPTP intoxication of non-human primates leads to a-synuclein inclusions (Kow-all et al., 2000). Since one of the early markers andfeatures of PD is a selective decrement in complex Ifunction (Mizuno et al., 1995; Schapira et al., 1998),understanding the mechanisms by which complex Iinhibitors kill dopaminergic neurons and how it leadsto the formation of a-synuclein inclusions may pro-vide tremendous insight into the pathogenesis of PD.

GENETICS IN PARKINSON’S DISEASE

A genetic cause for PD was fueled by the discoveryof Polymeropoulos and colleagues who identified analanine to threonine substitution at codon 53 (A53T) ina-synuclein in a large Italian–American kindred andin three Greek kindreds (Papadimitriou et al., 1999;Polymeropoulos et al., 1996, 1997). This was followedby the identification of a new mutation in a smallGerman PD pedigree caused by an alanine to prolinesubstitution at codon 30 (A30P) (Kruger et al., 1998).These mutations are exceedingly rare as they have notbeen identified in other familial kindreds nor do theyseem to be associated with the more common sporadicform of the disease (Chan et al., 1998; El-Agnaf et al.,1998a; Parsian et al., 1998; Vaughan et al., 1998; Wanget al., 1998).

Although genetic studies indicate that mutations ina-synuclein are a rare cause of familial PD, its impor-tance in PD pathogenesis is highlighted by the findingthat a-synuclein appears to be the primary componentof the Lewy body (Bayer et al., 1999; Spillantini et al.,1998b, 1997; Takeda et al., 1998; Trojanowski et al.,1998; Wakabayashi et al., 1998). Indeed, anti-a-
synuclein-antibodies stain Lewy bodies more in-

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tensely and consistently than any other antibodiesincluding anti-ubiquitin antibodies (Spillantini et al.,998b). Moreover, anti-a-synuclein immunoreactivity

is also abundant in pale bodies which are believed tobe precursor lesions of Lewy bodies (Irizarry et al.,1998; Wakabayashi et al., 1998). a-synuclein inclusionsre also prominent in other neurodegenerative disor-ers, which have prominent parkinsonian features

Gomez-Tortosa et al., 2000; Trojanowski et al., 1998).The nonamyloid-b component (NAC) of senileplagues in Alzheimer’s disease contains truncateda-synuclein (Ueda et al., 1993). NAC was recentlyshown to be selectively toxic for DA neurons (Forloniet al., 2000). Wild-type and mutant A53T and A30Pa-synuclein self-aggregate and assemble into approx-imately 10- to 19-nm-wide filaments with distinct mor-phology that resemble the major ultrastructural ele-ments of authentic Lewy bodies (Conway et al., 1998;El-Agnaf et al., 1998b; Giasson et al., 1999). Further-more, both wild-type and mutant a-synuclein formnsoluble fibrillar aggregates with anti-parallel b-sheet

structure upon incubation at physiologic temperaturein vitro and the aggregate formation is accelerated byboth PD-linked mutations (Conway et al., 1998, 2000a,2000b; El-Agnaf et al., 1998b; Giasson et al., 1999). TheA53T mutation fibrillizes more quickly than wild typea-synuclein whereas the A30P mutation fibrillizesmore slowly. However, both the A53T and A30P mu-tants oligomerize faster than WT a-synuclein (Con-way et al., 2000b). Thus, oligomerization ofa-synuclein may play a more important role in thepathogenesis PD. In any event, the intrinsic propertiesand propensity of wild-type, A53T, and A30Pa-synuclein to fibrillate, oligomerize, and aggregatemay have important implications in the formation ofLewy bodies and the pathogenesis of PD (Dawson,2000).

Although a-synuclein is implicated in the pathogen-esis of PD through familial-linked mutations and itsenrichment in the pathologic hallmark of PD, theLewy body, its normal physiologic functions are notknown. However, the a-synuclein homolog synelfin ofthe zebra finch has been implicated in synaptic plas-ticity as it undergoes dynamic changes in seasonalsong learning (Jin and Clayton, 1997). To gain a betterunderstanding of the normal physiologic functions ofa-synuclein, a number of groups have attempted toidentify proteins which interact with a-synuclein,through yeast two-hybrid screening. Engelender andcoworkers (Engelender et al., 1999) identified ana-synuclein-interacting protein designated synphi-
lin-1, which is a novel protein with ankyrin-like re-

peats, a coiled-coil domain and ATP, GTP-bindingdomain. a-synuclein was shown to interact both initro and in vivo with synphilin-1 in neurons. Cotrans-ection of NAC and synphilin-1 yields cytoplasmicosinophilic inclusions, which closely resemble thetructure of Lewy bodies (Engelender et al., 1999).ostmortem studies in patients with PD indicate thatynphilin-1 and a-synuclein are strikingly colocalized

in Lewy bodies (Wakabayashi et al., 2000). a-synucleinalso interacts and inhibits phospholipase D2 (PLD2)(Jenco et al., 1998). Ostrerova et al. (1999) observed thatregions of a-synuclein and 14-3-3 proteins share over40% homology and showed that a-synuclein binds toproteins that are known to associate with 14-3-3, in-cluding protein kinase C, BAD, and extracellular reg-ulated kinases. Furthermore, they showed that over-expression of a-synuclein inhibits protein kinase Cactivity. a-Synuclein is toxic and overexpression of theA53T or A30P mutations exhibit even greater toxicity(Ostrerova et al., 1999). Jensen and coworkers (1999)observed that the microtubule-associated protein, Tau,binds to a-synuclein and stimulates protein kinaseA-catalyzed phosphorylation of Tau serine residues262 and 356, which may indirectly affect stability ofaxonal microtubules. Microtubule-associated protein1B is a component of Lewy bodies and binds toa-synuclein (Jensen et al., 2000). a-Synuclein may turnout to have additional binding partners as it possessesa highly conserved amino-terminal repeat domain(KTKEGV), which may mediate lipid-binding anddimerization (Clayton and George, 1998). a-Synuclein

elongs to a family of structurally related proteinsncluding b-synuclein and g-synuclein (Clayton and

George, 1998). b and g-synuclein have been identifiedin presynaptic axonal terminal pathology in the hip-pocampus of Parkinson’s Disease and Lewy body de-mentia, implicating all three synucleins in neurode-generative synucleinopathies (Galvin et al., 1999b).

Mice lacking the a-synuclein gene display func-tional deficits in nigrostriatal dopamine systems (Abe-liovich et al., 2000). a-Synuclein knockout mice areviable, fertile, and exhibit normal brain structure, aswell as a normal complement of dopaminergic cellbodies, fibers, and synapses, nor do they possess aparkinsonian phenotype. Thus, a loss of function ofa-synuclein is unlikely to cause PD and suggests thatmutations in a-synuclein that cause PD are likely to begain a function of mutation (Abeliovich et al., 2000).Despite the lack of a parkinsonian phenotype in thea-synuclein knockout mice, they possess a reductionin striatal dopamine, and an attenuation of dopamine
dependent locomotor response to amphetamine and

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increased dopamine release following paired stimuli,which suggests that a-synuclein is an essential presyn-aptic, activity-dependent negative regulator of dopa-minergic neurotransmission (Abeliovich et al., 2000).In the rat optic nerve a-synuclein is carried by vesiclesthrough fast axonal transport. Mutant a-synuclein isincapable of vesicle binding and thus, mutations ina-synuclein might act as dominant interfering mu-tants that lead to a dysfunction of dopaminergic neu-rotransmission (Jensen et al., 1998).

Overexpression of wild-type a-synuclein in miceusing the platelet derived growth factor (PDGF) pro-moter yielded mice with selective decrements in DAnerve terminals in the striatum with a concomitantreduction in TH catalytic activity (Masliah et al., 2000).Both cytoplasmic and nuclear a-synuclein inclusionswere observed in the transgenic mice. Nuclear inclu-sions are atypical in PD. No a-synuclein containingfibrils were noted in the inclusions, which are a keyfeature of Lewy bodies. No loss of DA neurons, whichis another key feature of sporadic PD, was reported.The high expressing lines were impaired on rotorodperformance. Whether the impaired rotorod perfor-mance is due to dysfunction of DA neurons awaitsfurther study (Masliah et al., 2000). Feany and Bender(2000) recently described the generation of transgenicfruit flies over-expressing wild-type A53T or A30Pa-synuclein. All three transgenic lines develop an age-dependent loss of DA containing neurons, motor dys-function, and Lewy body-like inclusions. Both modelsrepresent a significant advance and suggest that dys-function of a-synuclein is involved in the pathogene-sis of PD and they provide new opportunities to dis-cover the mechanisms by which abnormalities ina-synuclein lead to selective DA neuron impairmentand death (Dawson, 2000).

Mutations in parkin are associated with autosomalrecessive juvenile parkinsonism (AR-JP) (Kitada et al.,1998). AR-JP was first described in Japan (Ishikawaand Tsuji, 1996; Mizuno et al., 1999). AR-JP patientsshow typical signs of PD, but it is associated with earlydisease onset typically before the age of 40, dystonia atonset, diurnal fluctuations, slow disease progression,and early and severe levodopa-induced dyskinesias(Ishikawa and Tsuji, 1996; Mizuno et al., 1999). In a fewcases, neuropathologic examination reveals severeloss of dopaminergic neurons in the SNC with theabsence of Lewy bodies (Mori et al., 1998). However,parkin is present in Lewy bodies in sporadic PD(Shimura et al., 1999). A number of homozygous de-letions and point mutations in parkin cause autosomal
recessive PD in families of Japanese, European and
Middle East origin (Abbas et al., 1999; Hattori et al.,998a, b; Leroy et al., 1998; Lucking et al., 1998). Somef the families identified have affected family mem-ers who are compound heterozygotes with separateutations on each allele leading to a PD phenotype

Abbas et al., 1999). Some of these patients with com-pound heterozygote mutations in parkin present withfeatures indistinguishable from idiopathic PD (Luck-ing et al., 1998). Mutations in parkin appear to accountfor the majority of autosomal recessive inherited PD(Lucking et al., 2000). The function of the parkin pro-tein remains unknown. However, parkin shows mildhomology to ubiquitin at the N-terminus and containstwo RING-finger motifs and an IBR domain (in be-tween RING finger) domains at the C-terminus (Mor-ett and Bork, 1999). The existence of two RING fingermotifs and the N-terminal homology to ubiquitin sug-gest that parkin may be involved in the ubiquitinationpathway. Recently, a few proteins with RING fingermotifs similar to parkin were shown to be involvedwith E-2-dependent ubiquitination (Joazeiro et al.,1999; Lorick et al., 1999). Thus, the two RING fingermotifs and IBR domain of parkin may provide anE-2-binding interface. Interestingly, several of thepoint mutations identified in parkin fall within thetwo RING finger domains implicating the importanceof the RING finger motif in parkin function (Abbas etal., 1999; Lucking et al., 1998).

Mutations in ubiquitin carboxy-terminal-hydro-lase-L1 (UCH-L1) have been reported to cause auto-somal dominant PD (Harhangi et al., 1999). UCHL-1 isa member of the ubiquitin C-terminal, hydrolase genefamily, which hydrolyzes small C-terminal adducts ofubiquitin to generate the ubiquitin monomer, thus it isinvolved with the degradation of proteins through theproteosome. UCHL-1 is an abundant brain protein asit accounts for 1 to 2% of total soluble brain proteinand it is present in all neurons (Lowe et al., 1990;Wilkinson et al., 1989). Despite the identification of theI93M missense mutation in the UCHL-1 gene in theGerman family with Parkinson’s Disease, comprehen-sive analysis of several PD family kindreds have notidentified this mutation in any other family, whichsuggests that the mutation in UCHL-1 is either a rarecause of PD or it is a harmless substitution whoseoccurrence in the family reflects a chance co-occur-rence (Harhangi et al., 1999; Maraganore et al., 1999).However, Sagioh et al. (1999) recently reported that aninframe deletion in exons 7 and 8 of the UCHL-1 genein mice leads to an autosomal recessive sensory andmotor ataxia characterized by axonal degeneration
and the formation of spheroid bodies in nerve termi-

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nals and the accumulation of amyloid-b and ubiquitindeposits. Thus, it is possible that dysfunction of theUCHL-1 gene could contribute to the formation ofLewy bodies and subsequent neuronal degenerationin PD by preventing or interfering with the appropri-ate degradation of ubiquitin-tagged proteins.

Mutations in Tau have been associated with thesyndrome of frontotemporal dementia, behavioral dis-turbances and parkinsonism (Mizuno et al., 1999; Spill-ntini et al., 1998a). Mitochondrial inheritance haseen suggested in some families and other familiesave been proposed to have anticipation (Mizuno etl., 1999; Wooten et al., 1997). Genetic analysis furtherndicates that familial PD is associated with geneticinkage to Chromosomes 2P and 4P, as well as yetnidentified loci (Farrer et al., 1999; Gasser et al., 1998;winn-Hardy et al., 2000).

IS IT POSSIBLE TO LINK IDIOPATHICPD WITH THE KNOWN MUTATIONSIN FAMILIAL-LINKED PD?

A consistent feature of idiopathic PD is the decre-ment in complex I function and indices of increasedoxidative stress. The decrements in complex I functionhas the propensity to create oxidative stress throughmitchondrial production of reactive oxygen species(Jenner and Olanow, 1998). Although MPTP intoxica-tion potently inhibits complex I and leads to the selec-tive degeneration of dopaminergic neurons, the acutenature of the intoxication may prevent the formationof Lewy bodies. Since wild-type a-synuclein has thepropensity to form fibrils, oligomerize and aggregate(Hashimoto and Masliah, 1999), it is conceivable thatthe oxidative stress generated by chronic complex Iinhibition in sporadic PD stress could promote thefibrilization, oligomerization, and aggregation ofa-synuclein and initiate the process of Lewy bodyformation. This model is substantiated by both in vitroand in vivo models. Both in vitro and in vivo experi-

ents indicate that oxidative stress promotesa-synuclein aggregation and inclusions (Hashimoto etal., 1999; Hashimoto and Masliah, 1999). Particularlystriking is the observation that MPTP administrationin nonhuman primates causes a-synuclein aggrega-tion and dopaminergic dysfunction and death (Kowallet al., 2000). Thus, oxidative and genetic induced alter-ations in a-synuclein may lead to a common pathway

f dopaminergic cell injury (Fig. 3).


ACKNOWLEDGMENTS

This work was supported by USPHS Grant NS38377, the EdwardO. and Anna Mitchell Family Foundation, and the U.S. Army Med-ical Research and Materiel Command. Under an agreement betweenthe Johns Hopkins University and Guilford Pharmaceuticals,T.M.D. and V.L.D. are entitled to a share of sales royalty received bythe university from Guilford. T.M.D. and the university also ownGuilford stock, and the university stock is subject to certain restric-tions under university policy. The terms of this arrangement arebeing managed by the university in accordance with its conflict-of-interest policies.

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Oxidative Stress and Genetics in the Pathogenesis of Parkinson's Disease