parkinson's disease: genetics and pathogenesis

PM06CH09-Shulman ARI 10 December 2010 12:12

Parkinson’s Disease: Geneticsand PathogenesisJoshua M. Shulman,1,3,4 Philip L. De Jager,1,3,4

and Mel B. Feany2,3

Departments of 1Neurology and 2Pathology, Brigham and Women’s Hospital, Boston,Massachusetts 02115; email: [email protected], [email protected] Medical School, Boston, Massachusetts 02115; email: [email protected] in Medical and Population Genetics, Broad Institute, Cambridge,Massachusetts 02142

Annu. Rev. Pathol. Mech. Dis. 2011. 6:193–222

First published online as a Review in Advance onOctober 25, 2010

The Annual Review of Pathology: Mechanisms ofDisease is online at pathol.annualreviews.org

This article’s doi:10.1146/annurev-pathol-011110-130242

Copyright c© 2011 by Annual Reviews.All rights reserved

1553-4006/11/0228-0193$20.00

Keywords

Lewy body, synuclein, genome-wide association study, animal model,LRRK2, GBA, MAPT, parkin

Abstract

Recent investigation into the mechanisms of Parkinson’s disease (PD)has generated remarkable insight while simultaneously challenging tra-ditional conceptual frameworks. Although the disease remains definedclinically by its cardinal motor manifestations and pathologically bymidbrain dopaminergic cell loss in association with Lewy bodies, itis now recognized that PD has substantially more widespread impact,causing a host of nonmotor symptoms and associated pathology in mul-tiple regions throughout the nervous system. Further, the discoveryand validation of PD-susceptibility genes contradict the historical viewthat environmental factors predominate, and blur distinctions betweenfamilial and sporadic disease. Genetic advances have also promotedthe development of improved animal models, highlighted responsiblemolecular pathways, and revealed mechanistic overlap with other neu-rodegenerative disorders. In this review, we synthesize emerging lessonson PD pathogenesis from clinical, pathological, and genetic studies to-ward a unified concept of the disorder that may accelerate the designand testing of the next generation of PD therapies.

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PD: Parkinson’sdisease

LB: Lewy body

SNCA: α-synucleingene

Familial PD: termused to characterizethe diagnosis of PD inthe setting of a knownfamily history of oneor more affectedrelatives; oftenassumed to representthe influence of genes

GWA: genome-wideassociation

INTRODUCTION

In his 1817 monograph An Essay on the Shak-ing Palsy, the British physician James Parkinson(1) published his observations of six individualswith “paralysis agitans.” Further refinement inour understanding of this syndrome, includingtremor, slowed movements, and gait impair-ment, was subsequently undertaken by Jean-Martin Charcot, who also coined the mod-ern label Parkinson’s disease (PD). In 1912,Friedrich Lewy (2), a German neurologist, de-scribed the cardinal neuropathological lesionthat would later bear his name: the Lewy body(LB). As we approach the 200-year anniversaryof the clinical recognition of this disease and the100-year anniversary of the key pathological in-sight, what would Dr. Parkinson and Dr. Lewythink today of the vast field of research that theirwork has spawned? In some ways, it has becomemore challenging than ever to answer the de-ceptively simple question “What is PD?”.

Despite tremendous progress on severalfronts—in fact, because of the advances by clin-icians, pathologists, geneticists, and others—the answer to this question often depends onone’s particular point of view. For example,does PD encompass the frequent finding of in-cidental LB pathology in the brain in the ab-sence of apparent clinical manifestations? Con-versely, what can we learn from cases that fitthe clinical profile of PD but fail to demon-strate typical autopsy findings? Further, how dowe integrate into our case definitions the recentwealth of evidence that genetics plays a key rolein disease susceptibility when, historically, apositive family history was an exclusionary con-sideration in diagnostic algorithms? Such ques-tions illustrate how progress can often chal-lenge traditional frameworks for understandingdisease. Fortunately, the confusion that accom-panies the crest of a rapidly advancing wave ofdiscovery is usually transient, and in its wakecomes a deeper understanding. We now know,for example, that the α-synuclein gene (SNCA),which encodes the primary constituent of theLB, influences susceptibility for rare familialPD as well as sporadic disease in the general

population. This key insight follows nearly acentury of investigation into PD, linking theearliest pathological observations of this disor-der to findings from the latest genome-wide as-sociation (GWA) studies. Given the currentlyrapid pace of discovery in PD research, thereis cause for optimism that many such excitingrealizations are imminent.

In this review, we aim to update the readeron progress in our understanding of PD genet-ics and pathogenesis, as well as to place recentresults in the context of the rich history of inves-tigation in this field. Throughout, we highlightexamples of discoveries that challenge existingconceptions of PD, and where possible, we tryto synthesize lessons from divergent lines of in-quiry. We begin with a review of our currentclinical and pathological understanding of PD,because a precise definition of the disease entitysubsequently guides our exploration of etiol-ogy. A coherent answer to the question “Whatis PD?” will facilitate the next generation ofgenetic advances and animal models and willhopefully propel translational research, therebyleading to novel neuroprotective and restora-tive therapeutic approaches.

EPIDEMIOLOGY ANDCLINICAL FEATURES

With a prevalence of approximately 1% at age65, which rises to nearly 5% by age 85, PD is thesecond most common neurodegenerative dis-order after Alzheimer’s disease (3, 4). The meanage of PD diagnosis is in the seventh decade oflife, but due to PD’s insidious nature, the onsetof symptoms may precede clinical recognitionby many years (5). PD can be diagnosed at anyage, and an estimated 3% of cases are initiallyrecognized in individuals younger than age50 (4). PD is typically a chronic and slowlyprogressive disorder with a mean duration of15 years from disease recognition until death,although affected individuals can frequentlysurvive two decades or longer (6, 7). Giventhe aging of the population, the prevalenceof PD is anticipated to increase dramatically,

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SN: substantia nigra

which would lead to increased urgency for theneed to identify improved therapies that delayprogression and mitigate disability.

The cardinal manifestations of PD includeresting tremor, bradykinesia (slowed move-ments), rigidity (increased muscular tone),postural instability, and gait impairment (7).Together, these manifestations produce thesyndrome of parkinsonism, of which PD isthe major cause; however, a similar clinical pic-ture can also accompany other neurodegener-ative disorders or nondegenerative conditions,including parkinsonism due to cerebrovascularinjury and medication-induced parkinsonism.As detailed below, PD motor manifestationsare attributable to dopaminergic cell losswithin the substantia nigra (SN) pars compactaand resultant dysfunction of the basal ganglia, acluster of deep nuclei that participate in the ini-tiation and execution of movements (Figure 1)(8). Indeed, motor symptoms respond wellto dopamine replacement therapy, whichhas been the pillar of PD treatment since itsintroduction in the late 1960s (7). In advanceddisease, direct modulation of basal gangliaactivity via deep brain stimulators implanted inthe subthalamic nucleus can also be effective.Although currently available PD therapies bothdelay disability and prolong life expectancy,none has been proven to significantly alter theongoing neurodegenerative process.

Motor features remain the essential criteriafor clinical diagnosis of PD and are a majorsource of disability, but PD has a much broaderimpact on the nervous system (9, 10). Nonmo-tor symptoms, including impaired olfaction,disordered sleep, and constipation, are nowbelieved to presage the clinical recognition ofbradykinesia, tremor, or gait impairment byas much as 20 years (5). As PD progresses,frequent motor freezing and falls, treatment-related involuntary movements (dyskinesias),pain and sensory complaints, autonomic dys-function (urinary incontinence and orthostaticintolerance), and neuropsychiatric manifesta-tions (depression, hallucinations, and demen-tia) become prominent, and these features areprobably due to the spread of pathology beyond

Dopaminergic input ExcitationInhibition

Healthy Parkinson’s disease

Pu

GPi

Th

SNc

GPe

Figure 1Anatomy and physiology of Parkinson’s disease (PD) motor manifestations. Asimplified schematic of the neuronal circuits involving the basal ganglia,thalamus, and cortex and their derangement in PD (8). For simplicity, only thedirect pathway is shown. It normally functions to facilitate movements (left),but in PD the output is attenuated (right). The midbrain substantia nigra parscompacta (SNc) provides dopaminergic input to the putamen (Pu), which isexcitatory to the direct pathway. The putamen inhibits (red ) the globus pallidusinterna (GPi), which subsequently inhibits the thalamus (Th). The thalamusprojects excitatory input ( green) to the motor cortex. In PD, degenerationwithin the SNc leads to net increased inhibition of the thalamocorticalprojection. The indirect pathway (not shown), including the globus pallidusexterna (GPe) and subthalamic nucleus, is inhibited by SNc dopaminergicinput and normally functions to repress movements, but its activity is enhancedin PD.

the basal ganglia (9, 10). Importantly, mostnonmotor symptoms show little or no responseto dopamine replacement and contributesubstantially to overall disability, especiallylate in disease (11). As detailed below, becausethe investigation of PD mechanisms, includingthe development of animal models, has focusedlargely on the vulnerability of dopaminergiccells in the SN, there remains an unmet need tounderstand how this disorder spreads beyondthe basal ganglia to other brain systems.

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In addition to advanced age, male gender,and European ancestry, a number of other epi-demiological factors have been proposed to in-crease PD risk (3). In 1983, a cluster of in-dividuals who developed a PD-like syndromefollowing abuse of intravenous drugs contam-inated with methyl-phenyl-tetrahydropyridine(MPTP) was discovered (12), and the hypoth-esis that exposure to environmental toxins mayincrease risk of developing PD has subsequentlyattracted intense interest. A meta-analysis of 19studies evaluating the potential impact of pes-ticide exposure found an estimated doublingof disease risk (13). Potentially consistent withthis finding, numerous mitochondrial toxins,including MPTP, the herbicide paraquat, andthe pesticide rotenone, cause dopaminergic cellloss in animal models, as reviewed further be-low. In addition, occupational or other expo-sure to heavy metals, including manganese andiron, has been suggested to increase PD risk,but epidemiological support for this hypothe-sis has been lacking (3). Many studies have alsoevaluated dietary and habitual factors, and bothcigarette smoking and coffee consumption areassociated with reduced PD susceptibility (14).Importantly, however, epidemiological associ-ation does not necessarily imply causation, andthe role of the basal ganglia in impulse controland reward mechanisms may predispose indi-viduals with PD to be less susceptible to engag-ing in addicting behaviors.

PATHOLOGY

The cardinal neuropathological feature of PDis dopaminergic cell loss within the SN in asso-ciation with the development of intracytoplas-mic, protein-rich inclusions termed LBs (15).As shown in Figure 2, the classic LB is spher-ical and eosinophilic, and it stains strongly forα-synuclein protein, which aggregates to formthe fibrillar core (16). On autopsy, the brainsof individuals with PD are additionally charac-terized by α-synuclein-positive accumulationswithin neuronal processes, termed Lewy neu-rites, as well as by neurons that show more dif-fuse or granular perikaryal staining patterns.

Because dopaminergic cells contain melanin,cell loss within the SN is accompanied by depig-mentation of the midbrain that is readily visiblein gross material postmortem.

Dopaminergic neurons in the SN projectprimarily to the striatum, which is composed ofthe caudate and putamen nuclei; therefore, α-synuclein pathology and associated nigral cellloss result in the depletion of striatal dopamine.As illustrated in Figure 1, decreased nigrostri-atal input leads to a net increase of inhibitoryoutput from the globus pallidus interna to thethalamus and, indirectly, to the cortex, therebyrepressing the initiation of movements andleading to the characteristic motor manifesta-tions of PD (8). Indeed, the severity of bradyki-nesia and rigidity in PD patients proximate todeath correlates with nigral cell loss and re-duced striatal dopamine levels found at autopsy(17). By the time PD motor symptoms are clini-cally recognized, 60% of dopaminergic SN cellsare lost, resulting in a concomitant 80% deple-tion of striatal dopamine. The progression ofthese changes can also be demonstrated in liv-ing patients by using nuclear imaging to mea-sure radiolabeled dopamine uptake in the stria-tum or by using tracer ligands that bind to thedopamine transporter (18).

In parallel with the growing appreciationthat, clinically, PD causes a host of nonmotormanifestations, it has been recognized thatα-synuclein pathology ranges beyond theSN into much of the neuraxis (19, 20).α-Synuclein pathology has been described inthe peripheral cutaneous nerves, autonomicnervous system, enteric nervous system, spinalcord, lower brainstem (dorsal motor nucleusof the vagus), limbic structures (amygdala andhippocampus), and neocortex. Importantly,the vulnerable cell populations include nu-merous nondopaminergic cell types, such asnoradrenergic neurons of the locus coeruleus,serotonergic projections from raphe nuclei,and acetylcholinergic cells of the basal fore-brain in the nucleus of Meynert. On the basisof a careful, postmortem analysis, Braak andcoworkers (20) proposed a staging system forPD pathology (Figure 3). Accordingly, the


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a b c

d e f

20 µm20 µm50 µm

20 µm20 µm20 µm

Figure 2Pathology of Parkinson’s disease. (a) Low-power view of the substantia nigra showing marked depletion ofdopaminergic neurons (arrow, remaining neuron), reactive gliosis, and neuromelanin present in phagocyticcells (arrowheads). (b) Typical brainstem-type Lewy body (LB; arrow) in a pigmented dopaminergic neuron.The LB has a characteristic dense eosinophilic core and surrounding paler halo. (c) Brainstem-type LBshowing staining for α-synuclein (arrow). (d ) Lewy neurites (arrows). (e) Cortical-type LBs (arrows) areindistinct with standard histological hematoxylin and eosin staining. ( f ) Cortical-type LB stain withantibodies against α-synuclein (arrows).

earliest Lewy pathology affects the entericand peripheral autonomic nervous system aswell as the olfactory bulb, and it subsequentlyspreads in a stereotyped, caudal-to-rostral wavefrom the lower brainstem (stage 1) to diffuseinvolvement of the neocortical ribbon (stage 6).In the Braak paradigm, α-synuclein pathologyis not observed in the midbrain SN until stage3, consistent with the building consensus that asubstantial prodromal syndrome precedes thedevelopment of PD motor symptoms and thesubsequent clinical recognition of the disorder(5). Further, the anatomic pattern of the earlierBraak stages fits remarkably well with proposedpremotor disease manifestations, includinghyposmia (olfactory bulb), constipation (en-teric nervous system), and sleep disorder(brainstem reticular formation) (19). In laterstages, widespread cortical involvement with

LBs correlates with the frequent occurrence ofcognitive impairment in long-standing PD.

Although it is now widely acknowledgedthat Lewy pathology can be found through-out the nervous system, the Braak proposalof a stereotyped caudal-to-rostral spread ofpathology remains an attractive hypothesis andawaits definitive confirmation (17). Althougha number of postmortem studies have vali-dated the Braak sequence, others have identi-fied a substantial minority of cases with patternsof pathology that diverge from the expecta-tions of the model (21, 22). Regardless, datafrom large cohort studies show that as manyas 20% of brains have evidence of LB pathol-ogy on autopsy; this figure is approximatelytenfold higher than the known prevalence ofPD. The finding of LBs on autopsy in the ab-sence of clinical evidence of neurologic disease


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Stages 1–2

Stage 3

Stage 4

Stages 5–6

C

A

SN

DM

RN

T

F Cingulate cortex (C)Temporal cortex (T) Frontal cortex (F) Parietal cortex Occipital cortex

Amygdala (A)Nucleus of MeynertHippocampus

Substantia nigra pars compacta (SN)

Dorsal motor nucleus of vagus (DM)

Raphe nucleus (RN) Locus coeruleus

Figure 3Progression of Parkinson’s disease (PD) pathology. Schematic outlining themajor stages of PD pathology, as proposed by Braak et al. (20). In stages 1–2,Lewy neurites and Lewy bodies are found within the medulla and pons. Only instage 3 does aggregated α-synuclein affect the substantia nigra. Later stages(4–6) involve the supratentorial compartment in a graded fashion, whichultimately leads to substantial neocortical pathology in stage 6.

DLB: dementia withLewy bodies

MSA: multiple systematrophy

proximate to death has been termed incidentalLB disease, and this population may representpreclinical PD. In support of this hypothesis,case series with incidental LB pathology werefound to have decreased nigral cell counts and

reduced striatal dopaminergic nerve terminals,intermediate between brains from subjects withknown PD and controls without α-synucleinpathology (23). Additional large clinical andpathological studies are needed to further ad-dress the intriguing hypothesis that incidentalLBs may represent the earliest stages of PD;ideally, such studies should include prospectiveassessment of premotor disease features alongwith neuroimaging studies of striatal dopamineuptake.

On the basis of the preceding discussion,PD can be clinically and pathologically definedas a progressive disorder comprising (a) acore of motor manifestations attributable toLB pathology and degenerative cell loss inthe SN and (b) a halo of nonmotor features,many of which precede the motor symptomsand probably result from more widespreadLewy pathology throughout the peripheral andcentral nervous systems. However, PD is themajor, but not the only, cause of parkinsonism.We briefly consider the other parkinsonian dis-orders here, as the marked clinical and, in somecases, pathological similarities may hold impor-tant clues to understanding PD pathogenesis.Some diseases, including dementia with Lewybodies (DLB) and multiple system atrophy(MSA), are also associated with α-synucleinpathology and are therefore classified alongwith PD as α-synucleinopathies. DLB is char-acterized clinically by parkinsonism and earlydevelopment of dementia, often accompaniedby prominent visual hallucinations and fluc-tuations in arousal (24). Pathologically, DLBshows widespread α-synuclein deposition,prominently involving the neocortex; examplesof cortical LBs are shown in Figure 2e,f.MSA is a more rapidly progressive disorderconsisting of prominent failure of the au-tonomic nervous system, including urinaryincontinence and orthostatic intolerance,accompanied by parkinsonism and/or cere-bellar dysfunction and associated with glialα-synuclein inclusion pathology (Figure 4a).

In addition to the α-synucleinopathies,several other disorders frequently associatedwith parkinsonism are characterized by Tau


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a b c

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Figure 4Pathology of other disorders that cause parkinsonism. (a) Typical oligodendroglial inclusion (arrow) ofmultiple system atrophy stained with an antibody to α-synuclein. (b) The substantia nigra from a patientwith progressive supranuclear palsy shows depletion of dopaminergic neurons, reactive gliosis, andneuromelanin present in phagocytic cells (arrowheads). A remaining neuron contains an indistinct roundinclusion (arrow). (c) Immunostaining for Tau reveals a globose neurofibrillary tangle (arrow) that is typicalof progressive supranuclear palsy and corticobasal degeneration. (d ) Neuronal inclusion (arrow) from apatient with frontotemporal dementia, stained with an antibody against ubiquitin. (e) The pathology ofneurodegeneration with brain iron accumulation includes spheroids (arrow) and iron pigment deposition(arrowhead ). ( f ) A well-organized infarct shows loss of brain parenchyma with central cavitation (arrow)surrounded by reactive astrocytes (arrowheads).

pathology and are collectively referred to astauopathies. Tau is a neuronal microtubule-associated protein, and like α-synuclein, it canaggregate to form intracytoplasmic pathologicinclusions associated with neurodegeneration(25); examples are shown in Figure 4b,c. Cor-ticobasal ganglionic degeneration (CBD) andprogressive supranuclear palsy (PSP) are twotauopathies that can be difficult to clinically dis-tinguish from PD at onset; however, symptomsgenerally respond poorly to dopamine replace-ment, and as the disease progresses additionalcharacteristic features develop. Parkinsonismcan also be observed in association with thefrontotemporal dementias, which are a group ofdisorders characterized primarily by profound

and heterogeneous cognitive manifestations(26). At autopsy, frontotemporal dementiacases generally reveal either Tau pathology orintranuclear inclusions that stain positive forubiquitin and the TAR-DNA-binding proteinTDP-43; an example is shown in Figure 4d.Tau pathology is perhaps best known for itsassociation with Alzheimer’s disease, in whichTau aggregates to form neurofibrillary tanglesconcomitant with the development of amyloidplaques. Parkinsonism is also common inAlzheimer’s disease, and in some cases, motormanifestations have been associated withTau pathology in the SN (27). Finally, thereare at least two examples of tauopathy andparkinsonism that result from environmental


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Geneticheterogeneity:occurs when the samedisease phenotype canbe caused by distinctsets of genetic variants;characteristically seenin complex genetictraits

Penetrance:the proportion ofindividuals with agenotype that manifestthe associatedphenotype

Sporadic PD: themost common form ofPD; occurs in theabsence of a knownfamilial history and isoften assumed toreflect the absence ofsignificant geneticcontribution

triggers. A major cause of PD-like illness in theearly twentieth century was postencephaliticparkinsonism, in which nigral neurofibrillarytangles and neurodegeneration followedinfluenza infection (28). Similarly, the Guamparkinsonism and dementia complex, a rareindigenous parkinsonian disorder, has beenlinked to a neurotoxin in the cycad fruit (29).

In some cases of neurodegenerative parkin-sonism, nigral cell loss and gliosis are observedwithout any other specific pathology, includ-ing the absence of α-synuclein, Tau, or otherprotein inclusions, and this pattern is typicalfor certain Mendelian disorders, as detailed be-low. Lastly, parkinsonism can also be observedin nondegenerative conditions, and one com-mon cause is cerebrovascular disease. Patholog-ically, vascular parkinsonism is associated withischemia-related cell loss and gliosis involv-ing the basal ganglia (Figure 4f ). Understand-ing how nonsynuclein pathologies contributeto parkinsonian syndromes may provide key in-sights into the mechanisms of cell vulnerabilitywithin the SN that could ultimately be trans-lated into improved understanding and treat-ment of PD. In addition, because autopsy stud-ies in aging populations commonly show mixedpathologies, it will be important to determinewhether α-synuclein pathology may interactwith other neuronal insults to modify the onsetand progression of PD in an individual patient.

GENETICS

The past decade has witnessed a remarkabletransformation in our understanding of therole of genetics in PD pathogenesis. PD hashistorically been considered a sporadic disorderin which environmental triggers played a dom-inant etiologic role; this view was influenced inpart by the 1980s outbreak of MPTP-inducedparkinsonism (12). The traditional tools ofgenetic epidemiology, twin studies and familialaggregation, have produced conflicting resultsin PD, adding to the skepticism that genes hadsignificant influence (3). However, such studiesmay be ill-equipped to detect genetic effects insome complex traits, such as PD in which ge-

netic heterogeneity and incomplete penetrancemay predominate. Further, given the strong in-fluence of aging, underestimates of heritabilityprobably come from either the failure to followsubjects to a sufficiently advanced age or thesubjects’ premature death before PD symptomsmanifest. Indeed, heritability estimates in PDsubstantially increase when young-onset dis-ease is considered, which probably magnifiesthe effects of more penetrant loci. Amongseveral more recent epidemiological studies,10–30% of PD subjects reported a positivefamily history, and first-degree relatives ofsubjects with PD were estimated to have atwofold- to sevenfold-increased relative riskof PD (30, 31). In a study of PD concordancein monozygotic versus dizygotic twins, heri-tability was estimated to vary from zero to one,depending on whether older- or younger-onsetdisease was considered, respectively (32). Onthe basis of the empirical findings of geneticstudies in PD, discussed below, it appears thatepidemiological methods have substantiallyunderestimated the genetic contribution toPD. For example, familial PD, in which thereis a known family history, has traditionallybeen differentiated from sporadic disease,where genetics is assumed to play a minorrole. However, such distinctions are becomingincreasingly blurred, as several examples ofgene variants were initially identified in PDfamilies and subsequently found in substantialproportions of apparently sporadic PD cases.

Two primary methods have been used tosearch for PD genes. The first, linkage anal-ysis, tracks the segregation of chromosomal re-gions in pedigrees with multiple affected fam-ily members. This approach is most effectiveat identifying rare genetic variants that havehighly penetrant effects and are characterizedby Mendelian patterns of disease inheritance(33). The second method, association anal-ysis, uses a simple comparison of case andcontrol subjects to identify distortions in thefrequency of genetic variants in each group.This method has greater statistical power forthe discovery of common variants of mod-est effect sizes and incomplete penetrance, as


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Single-nucleotidepolymorphism(SNP): genomicvariant in which asingle base in the DNAdiffers from the usualbase at that position

Expressivity: thedegree to which aparticular genotype ismanifest in thephenotype

Mendelian PD: arare form of familialPD characterized bymultiple affectedfamily members in apedigree consistentwith an autosomaldominant or recessiveinheritance pattern

Dystonia:characterized byinvoluntary twistingmovements andabnormal posturescaused byinappropriate andsustainedcocontraction ofagonist and antagonistmuscle groups

illustrated by the discovery of many such sus-ceptibility loci in a variety of common butgenetically complex disorders (34). The fullpotential of this approach was realized by theavailability of high-density single-nucleotidepolymorphism (SNP) genotyping arrays thatinterrogate the contribution of common se-quence variation (frequency >5%) across thegenome in an unbiased manner.

The challenges of discovering PD-susceptibility genes are similar to thoseencountered by epidemiological studiesevaluating for evidence of heritability. Onepotential confounder is etiologic heterogene-ity: Parkinsonism is a common feature ofother neurodegenerative and nondegenerativedisorders, and such entities may be difficultto distinguish clinically from PD withoutautopsy confirmation. Perhaps an even greaterpotential problem is the growing evidence thatPD motor symptoms may develop only afteryears of ongoing neurodegenerative cell loss inthe SN and elsewhere in the nervous system(5). The tempo of pathological progressionand the ultimate age of PD symptom onsetmay be manifestations of variable disease ex-pressivity. As mentioned above, the prevalenceof incidental Lewy pathology in individualswithout recognized PD proximate to death isas high as 20% (17). If genetic variants act toincrease α-synuclein pathology, which subse-quently produces the clinical manifestations ofdisease, significant numbers of control subjectswith substantial pathology and subclinicaldisease might significantly dilute the power ofassociation analyses.

Fortunately, despite these potential hurdles,linkage analyses have successfully identified anumber of highly penetrant genetic variants(33), and recent GWA studies have discoveredadditional susceptibility loci of more modest ef-fect sizes that meet rigorous statistical thresh-olds and have been independently replicated(35, 36). Remarkably, in several cases, these twoapproaches have identified both high- and low-penetrant genetic variants affecting the sameloci, linking the etiology of Mendelian PD inrare families with the genetics of sporadic PD in

the general population. Therefore, the conver-gence of findings from traditional approaches(linkage analysis) and more modern, complexgenetic methods (GWA analysis) reveals a con-tinuum of disease risk from sporadic to famil-ial disease, upon which age, environment, andstill-unknown genetic factors probably interactto manifest disease (Figure 5).

As with the question “What is PD?”, nearlyas much controversy is engendered by the re-lated question “What is a PD gene?”. We adoptthe guiding principles that a PD gene mustcause a syndrome with substantial clinical over-lap with PD, as delineated above, and that theresultant disorder must be characterized pre-dominantly by α-synuclein pathology on au-topsy. In applying these criteria, we have triedto determine whether both a neurologist anda pathologist, absent knowledge of the familyhistory and genotyping, might diagnose thesecases as PD (Table 1). Following our discus-sion of these PD genes, we discuss a largergroup of loci, collectively termed parkinson-ism genes, that cause parkinsonian syndromesbut with additional clinical features atypical forPD, and/or with distinct pathologies, or in somecases, where the pathology is not yet known. Asimilar scheme of classifying the growing listof genes relevant to PD has been suggestedby others (15, 37). Notably, the naming of PDloci has been largely historical and defers littleto such clinical and pathologic criteria. There-fore, some of the PARK genes cause syndromeswith only limited resemblance to PD, and otherparkinsonism genes have been subsumed underalternative naming schemes, such as those usedfor spinocerebellar ataxias or dystonias (38).

A systematic definition of PD, includingclinical, pathological, and genetic dimensions,is important for the field. Although knowledgeof a specific genetic etiology is not likely toimmediately impact patient treatment, in thenear future genotyping might realistically findits way into clinical practice, for example, in theform of diagnostic and prognostic algorithms,or for risk stratification of patients with knownfamily histories. In addition, identifying a pop-ulation of subjects with increased genetic risk


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Known genetic variants

Familial Sporadic

Environment andunknown genetic variants

Age

Diseaserisk

Disease threshold

SNCA mutations

LRRK2 R1441C, G2019S

LRRK2 R1628PC, G2385RMAPT H1

SNCA REP1

SNCA, MAPT, LRRK2, PARK16,

BST1 polymorphism

s

GBA mutations

Figure 5The emerging genetic architecture of Parkinson’s disease (PD). A model summarizing the relative effect sizesof known PD-susceptibility genes and illustrating possible interactions with age; potential environmentalrisk factors; and other, unknown genetic modifiers. The discovered genetic variants include both highlypenetrant Mendelian alleles that cause familial PD and polymorphisms with modest effects on disease riskthat contribute mainly to sporadic disease. In several cases, high- and low-penetrant variants were identifiedin the same loci. The known genetic variants form a continuum of risk for PD that, coupled with the effectsof age, environment, and other genes, blurs the distinction between familial and sporadic disease.

of PD might be crucial to successful trials ofemerging neuroprotective therapies. Finally, acoherent disease definition helps organize andcrystallize hypotheses about mechanisms of dis-ease, thereby informing subsequent investiga-tion, including animal model development and,ultimately, therapeutic innovation.

The α-Synuclein GeneThere is overwhelming evidence that SNCA,which maps to chromosome 4q21 and was ini-tially identified as the PARK1 locus, causes PDboth in families with rare Mendelian forms ofdisease and in sporadic cases. In 1997, linkageanalysis of an Italian family with autosomal

Table 1 Parkinson’s disease–susceptibility loci

Genetic variants (penetrance)

Locia Chromosome Full Partialb Reference(s)SNCA (PARK1/4) 4q21 A53T, A30P, E46K duplication,

triplicationREP1, rs2736990, rs11931074 35, 36, 39–41, 44, 45

LRRK2 (PARK8) 12p12 R1441C/G/H, I2020T, Y1699C,G2019S

R1628P, G2385R, rs1994090 35, 60, 61, 64, 78, 80

GBA 1q21 — N370S, L444P, others 92MAPT 17q21 — H1 haplotype, rs393152 36, 97BST1 4p15 — rs4538475 35PARK16c 1q32 — rs947211, rs823128 35, 36

aThe susceptibility loci PARK10 (159), PARK11 (160), and PARK12 (161), as well as PARK3 (162), which causes autosomal dominant Parkinson’s disease,have been identified as significant results of linkage studies but await validation and identification of the causal genes.bMany of these polymorphisms are probably markers for the true causal variants, which remain to be defined.cThe PARK16 locus contains five gene candidates.


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Causal variant:DNA-sequencechange that isfunctionallyresponsible forgenerating aphenotype

dominant PD led to the identification of theA53T mutation in SNCA, and subsequent stud-ies have identified two additional mutationsin other families (A30P and E46K) (39–41).Clinically, SNCA mutations cause disease onsetduring the fourth or fifth decade of life, withinitially asymmetric development of bradyki-nesia and rigidity and an excellent response todopamine replacement therapy that is similarto that of idiopathic PD (42). However, SNCAmutations are associated with a relatively rapidprogressive course and, frequently, the earlydevelopment of dementia similar to DLB. Atautopsy, these cases demonstrate widespreadα-synuclein pathology involving the brain-stem, limbic areas, and neocortex, as observedin later–Braak stage PD cases, with associateddopaminergic cell loss in the SN. Shortly afterthe SNCA mutations were found, α-synucleinprotein was first demonstrated to be a majorcomponent of the LB (43). This findingestablished a key link between the cause of rarefamilial disease and the defining neuropatho-logical lesion of PD in the general population.

Subsequent to the discovery of SNCA mu-tations, additional families believed to harbordominantly inherited mutations in a separatedisease-causing locus, PARK4, were found tohave genomic duplication or triplication of theSNCA gene, which led to a corresponding 50%or 100% increase in the dose of α-synucleinmessenger RNA and protein (44–46). SNCA lo-cus multiplication causes a heterogeneous clin-ical syndrome that ranges from a late-onsetpresentation indistinguishable from idiopathicPD to early-onset parkinsonism in associationwith dementia and/or autonomic dysfunction;these syndromes are typical of DLB and MSA,respectively (47). In addition, as has been re-ported for SNCA mutation carriers, gene mul-tiplication can also lead to the manifestation ofnonmotor PD symptoms, including abnormalolfaction and sleep disturbance (42, 48). As ex-pected, autopsy studies of SNCA locus mul-tiplication cases demonstrate widespread LBpathology similar to that observed in PD, aswell as in DLB and MSA.

Given its involvement in familial PD, theSNCA gene became an excellent candidate sus-ceptibility locus for PD in the general popu-lation. Association studies soon suggested thatvariation in the length of a dinucleotide re-peat near the SNCA gene promoter (REP1)both augments α-synuclein expression (49) andmodestly increases the risk of disease (50–52).In a large meta-analysis in subjects of Europeanancestry, including more than 2,500 PD casesand a similar number of controls, the extended263-bp REP1 allele was associated with an oddsratio of 1.4 for PD (53). REP1 is present inapproximately 5–10% of the population stud-ied and was therefore estimated to account fornearly 3% of the risk for PD in individuals ofEuropean ancestry. Whereas initial investiga-tions of the REP1 allele were hypothesis driven,the SNCA gene was recently validated as a PD-susceptibility locus in several GWA studies (35,36, 54, 55). In the largest study in subjects ofEuropean ancestry to date, involving more than5,000 cases and 8,000 control subjects, multipleSNPs at the SNCA locus showed highly signifi-cant associations with PD (36). The best SNP inthis study, rs2736990, was associated with onlya modest increased risk of disease (odds ratio =1.2, P = 2.2 × 10−16); however, the risk alleleat this marker is present in nearly half of theCaucasian population. In an independent studyconducted in Japanese subjects, including morethan 2,000 cases and 18,000 controls, commonvariation at SNCA was also implicated in sus-ceptibility to PD (35). The discovered associ-ation signals localize near the 3′ region of theSNCA gene and show partial linkage disequi-librium with REP1, which raises the possibilitythat these variants may be different surrogatemarkers of a single causal variant, possibly af-fecting gene expression.

α-Synuclein is a small, 140–amino acidprotein that contains an amphipathic amino-terminal domain, a hydrophobic central core[the nonamyloid component (NAC) region],and a negatively charged C terminus (56). Itis widely expressed throughout the nervoussystem and is enriched at presynaptic nerve


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Gain of function:a genetic variant thatalters function orexpression, rather thansimply causing aknockout of activity;usually associated withdominant inheritance

LRRK2: leucine-richrepeat kinase 2 gene

terminals, where it is found in associationwith synaptic vesicular membranes. Thus,α-synuclein may function in regulating synap-tic transmission and/or neuronal plasticity,although in mouse knockout studies, thegene is dispensable for both viability andnervous system development, and these an-imals do not show any gross motor or otherbehavioral abnormalities (57). However, thehuman genetic findings outlined above suggestthat α-synuclein promotes PD pathogenesisthrough gain-of-function mechanisms, eitherthrough dominantly inherited mutations orvia gene-multiplication or gene-promoterpolymorphisms that increase expression.α-Synuclein is normally in a soluble andunfolded state, but it is capable of adoptinga β-pleated sheet conformation that favorspolymerization into fibrils, as is typical of otheramyloidogenic proteins (58). Significantly,both disease-causing mutations, A53T andE46K, cause increased in vitro rates of fibrilformation that is structurally similar to that ofthe aggregated α-synuclein found in LBs (56,59). However, growing evidence suggests thatsmaller α-synuclein oligomers may constitutethe neurotoxic species; this view draws supportfrom animal model studies, as discussed below.

Leucine-Rich Repeat Kinase 2

Mutations in the leucine-rich repeat kinase 2gene (LRRK2) on chromosome 12, originallydesignated as the PARK8 locus, were firstidentified after linkage analysis and positionalcloning methods were applied to isolated fam-ilies with autosomal dominant parkinsonism(60, 61), but variants in this gene were subse-quently discovered to be a common contributorto PD risk in both sporadic and familial cases(62–67). To date, nearly 50 different LRRK2variants, mostly missense mutations, have beenreported to be associated with disease, andadditional sequencing of this locus in largenumbers of cases and controls will be requiredto comprehensively define the allelic spectrumand understand the full impact of this locuson the overall burden of PD. Of the large

number of described variants, broad consensushas thus far been reached on the pathogenicityof a subset including R1441C/G/H, I2020T,Y1699C, and G2019S, which occur at highlyconserved residues and appear to have func-tional consequences, but the list of validatedcausative alleles is likely to grow (63). Thegenetic architecture of the LRRK2 locus iscomplicated; the contribution of individual riskalleles is strongly dependent on the ancestry ofthe population studied. For example, the mostcommon and best-studied variant, G2019S,is found at a frequency of 1% to 4% in PDpatients of European descent (68). However,whereas this allele is virtually absent in Chineseand Japanese populations, it is a major causeof disease in Portuguese, Ashkenazi Jewish,and North African Arab patients, in whom itis found at frequencies of 6%, 15%, and 40%of PD patient cohorts, respectively (69–71).Frequency estimates are even higher when PDcases with known family history are selectivelyconsidered; however, as alluded to above, thisdistinction between sporadic and familial dis-ease is probably misleading. The data stronglysuggest that LRRK2 variants are inheritedancestral polymorphisms, as opposed to denovo mutations (72, 73); therefore, the absenceof family history in apparently sporadic casesis probably due to a number of confounders,including incomplete reporting, unrecognizedor subclinical disease, premature death fromother causes, the strong effect of age on diseasemanifestation, and the probable impact ofenvironmental and other genetic modifiers.

In large patient cohorts in which commonLRRK2 mutations (mostly G2019S) have beendiscovered, the presentation and course of dis-ease is consistent with idiopathic PD. LRRK2-associated disease has a mean onset age ap-proaching 60 years and may be associated witha slightly more benign, tremor-predominantdisease course (68). In one of the initial re-ports in the Basque population, the LRRK2gene was named dardarin, which is derivedfrom the Basque word for tremor (60). Non-motor manifestations, including impaired ol-faction, urinary symptoms, constipation, and


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GBA:glucocerebrosidasegene

depression, are commonly described in LRRK2-associated disease (66, 68). The initially de-scribed rare familial variants and the more com-mon G2019S polymorphism behave geneticallyas highly penetrant risk alleles; however, ageappears to be a key factor in disease man-ifestation, suggesting the possibility of vari-able expressivity. In a large study of G2019S-associated disease, penetrance increased from30% at age 60 to nearly 75% by age 80 (68).This mutation is extremely uncommon in oldercontrol populations; however, isolated cases ofasymptomatic G2019S carriers as old as 80have been described (74). The predominantpathology of LRRK2-associated disease is con-sistent with that of idiopathic PD and includesLB formation and associated neurodegenera-tion within the SN and other vulnerable brainregions (65, 75). Notably, there have been iso-lated reports of alternate pathologies associatedwith LRRK2 mutations, including tauopathy,ubiquitin-positive pathology, and nonspecificnigral degeneration in the absence of inclusions(61, 76, 77). Further study will be required tounderstand the full clinical and pathologic spec-trum of LRRK2-associated neurodegenerativedisease.

The allelic spectrum within the LRRK2 geneextends beyond less common and highly pene-trant variants; association analyses have foundthat this locus also harbors susceptibility alleleswith more modest effects on PD risk. The best-validated examples include the R1628P andG2385R variants in Chinese and Japanese pop-ulations (78–80). These two variants, present inapproximately 5–9% of PD cases of East Asiandescent (compared to ∼3% of controls), areeach associated with an approximately twofold-increased risk of disease; together, these vari-ants are estimated to explain ∼10% of the riskof sporadic PD in this population (33). In addi-tion, a large GWA study conducted in Japanesesubjects recently identified a highly signifi-cant association between SNPs in the LRRK2genomic region with risk of PD (rs1994090,odds ratio = 1.4, P = 2.7 × 10−8) (35). TheG2385R and R1628P variants are not foundin subjects of European descent, and initial

candidate association studies to investigate thecontribution of more common LRRK2 vari-ants in this population were equivocal (81).However, in a recent large GWA study (36),polymorphisms within the LRRK2 locus dis-played suggestive evidence of association withsusceptibility to PD in individuals of Euro-pean ancestry (rs1491923, odds ratio = 1.1,P = 1.6 × 10−5). Additional genotyping in evenlarger population samples will therefore be re-quired to validate this finding and to identifythe causal variant(s) within LRRK2 responsiblefor this association.

LRRK2 is a complex locus that comprises 51exons and encodes a large and structurally un-usual 2,257–amino acid protein that includesleucine-rich repeats, a Ras-like GTPase domain(ROC), C-terminal of ROC domain (COR), ki-nase domain, and WD40 motif (60, 61, 63).The LRRK2 protein is widely expressed in bothneuronal and nonneuronal tissues, and a sub-stantial fraction of protein appears to be mem-brane associated (82). Confirmed pathogenicmissense mutations in LRRK2 affect theGTPase (R1441C/G/H), COR (Y1699C), andkinase domains (G2019S, I2020T), and severalreports suggest that these substitutions impactenzymatic activity (63). Importantly, the mostcommon and best-studied variant, G2019S, in-creased kinase activity in a number of assays(83), consistent with a toxic, gain-of-functionmechanism for LRRK2-associated PD for thisallele. LRRK2 protein is capable of autophos-phorylation, and several other potential sub-strates have been nominated on the basis of avariety of experimental approaches (63). Addi-tional study will be required to identify the invivo LRRK2 substrate(s) relevant to health anddisease; some early insights from animal modelsare described below.

Glucocerebrosidase

Gaucher’s disease is an autosomal recessive,lysosomal storage disorder caused by loss offunction of the glucocerebrosidase gene (GBA)on chromosome 1; nearly 300 distinct muta-tions have been identified to date (84). GBA


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MAPT: microtubule-associated protein Taugene

catalyzes the conversion of the glycolipid glu-cocerebroside to glucose and ceramide, and theabsence of this enzyme leads to a multisys-tem disorder that in some cases includes neu-rologic manifestations. A connection betweenGBA and PD was first suggested by observa-tions that patients with Gaucher’s disease candevelop parkinsonian features (85, 86) and thatrelatives of Gaucher’s patients who are carriersfor disease-causing mutations appeared to haveincreased susceptibility for PD (87). As theseobservations became more widely recognized,many reports emerged on the unexpectedly fre-quent discovery of GBA mutations in clinic pop-ulations of sporadic PD patients (88–91); thesefindings culminated in the recent publicationof a large, collaborative case/control compari-son that involved more than 5,000 PD patientsand a similar number of controls (92). Becauseof a founder effect, GBA mutations are morecommon in Ashkenazi Jewish individuals, andtwo common mutations, N370S and L444P,were discovered in 15% of PD patients com-pared with 3% of controls. In non-Ashkenazisubjects, the same mutations were dispropor-tionately discovered in 3% of patients and lessthan 1% of controls. However, full sequenc-ing of the GBA gene led to the identification ofmany more polymorphisms, increasing the al-lele frequency to 7% among non-Ashkenazi pa-tients. The study-wide odds ratio for any GBAallele was nearly 6.5 (92), and other reportssuggest that less common, more highly pene-trant variants may be associated with a greater-than-tenfold-increased risk of disease (91). Im-portantly, only a minority of PD patients withGBA alleles (24%) reported a known familyhistory of disease, again challenging the dis-tinction between familial and sporadic disease.Clinically and pathologically, the PD pheno-type in GBA-variant carriers closely matchesthat found in patients with idiopathic disease(93), although the age of onset is earlier, with amean of 55 years in the largest study (92).

Based on the discovery of GBA risk allelesin a small but appreciable number of asymp-tomatic controls, current evidence supports ei-ther a strong susceptibility locus or a Mendelian

dominant locus with incomplete penetrance.However, the challenge in precisely determin-ing the penetrance of GBA, as well as of othersusceptibility loci, is to establish large controlcohorts of sufficiently advanced age; doing sorequires a careful and thorough assessment forparkinsonian signs and ideally includes screen-ing for premotor features of PD. Ultimately,it will also be important to evaluate for riskalleles in large numbers of controls with au-topsy data to determine whether there is an as-sociation with LB pathology. It remains possi-ble that GBA, and other susceptibility loci withapparently incomplete penetrance, will showincreased penetrance when considering apathological definition of disease, inclusive ofincidental Lewy pathology.

The example of the Ashkenazi Jewish popu-lation underscores how transformative geneticshas been in our understanding of PD etiology.We now recognize that in cohorts of AshkenaziJewish PD patients, approximately 20% haveGBA mutations (91, 92) and at least 15% haveLRRK2 mutations (68, 71). Interestingly, in co-horts where both GBA and LRRK2 were geno-typed, disease-causing variants rarely occurredtogether in the same subjects—significantlyfewer than would be expected by chance (91,94). Therefore, in this population, more thanone-third of PD cases appear to be accountedfor by genetic causes that are potentially com-patible with a Mendelian, monogenic inheri-tance model of disease. Given that only a fewyears ago, the existence of substantial heritabil-ity in PD was widely doubted, this observationshould caution against reaching a prematureconclusion on the ultimate genetic architectureof PD in Ashkenazi Jewish or other populations.

Microtubule-Associated Protein Tau

The microtubule-associated protein Tau gene(MAPT ) has long been of interest in neu-rodegenerative disease, given that the en-coded protein Tau aggregates to form neu-rofibrillary tangles, a pathological hallmark ofAlzheimer’s disease, and also forms filamen-tous pathological inclusions that characterize


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several other neurodegenerative disorders, col-lectively termed tauopathies (25, 95). As de-scribed above, parkinsonism is a common clin-ical accompaniment to tauopathy, and in 1998,mutations in MAPT were identified in onesuch disorder: familial frontotemporal demen-tia with parkinsonism linked to chromosome17 (FTDP-17) (96). This finding prompted ef-forts to determine whether genetic variation atthe MAPT locus might impact other neurode-generative disorders with similar clinical and/orpathological features. An extended haplotype atthe MAPT locus, termed H1, was demonstratedto increase risk for both PSP and CBD, and sub-sequently, many groups reported suggestive as-sociations in PD case/control cohorts (95, 97).In a recent, large collaborative study that in-volved nearly 2,000 cases and a similar numberof controls, homozygosity for the H1 haplotypewas found to increase disease risk by nearly 50%(98). Given that H1 is the common haplotypein populations of European ancestry, it maycontribute to a substantial burden of PD. Re-cently, several GWA studies in PD subjects ofEuropean descent validated the association be-tween the MAPT locus and PD risk (36, 54, 55).In the largest and best-powered analysis (36),several SNPs in linkage disequilibrium withthe H1 haplotype were discovered with highlysignificant association statistics (rs393152,odds ratio = 0.8, P = 2.0 × 10−16). Interest-ingly, this association signal was not observed ina similarly powered GWA analysis in Japanesesubjects, which further suggests that there is ge-netic heterogeneity in PD pathogenesis acrossdifferent populations (35).

Although the mechanism of the H1 haplo-typic association with PD remains unknown,several studies suggest that the risk haplotypemay increase gene expression at the MAPT lo-cus and may also lead to differential expressionof alternative transcripts (95, 99, 100). How-ever, because the implicated region on chromo-some 17 is large (900 kb) and may affect genesin addition to MAPT, future studies of largercohorts should aim to further refine the asso-ciation signal and unambiguously identify thecausal gene and variant(s). Because mutations

in MAPT cause a syndrome, FTDP-17, that isclinically and pathologically distinct from PD,how variation at one locus might trigger twosuch divergent disorders is unknown. Never-theless, the involvement of MAPT in PD addsto the accumulating evidence of a mechanisticlink with Alzheimer’s disease and other neu-rodegenerative tauopathies.

Emerging Loci from Genome-WideAssociation Studies

As mentioned above, GWA studies provide apowerful method to scan the genome in anunbiased fashion to identify common variantsunderlying disease susceptibility, and this ap-proach has been successfully used to survey thegenetic architecture of numerous complex ge-netic disorders (34). The first PD GWA studieswere small (101, 102), including several hun-dred cases and controls, and therefore lackedstatistical power to identify susceptibility lociof modest effect sizes. Nevertheless, these stud-ies were among the earliest GWA studies per-formed in any neurodegenerative disorder, andmore recently, the data have been incorporatedinto larger meta-analyses (54, 103). In 2009,two large PD GWA studies were reported, eachincluding several thousand cases and controls,making them the best-powered studies to date(35, 36). The rediscovery of SNCA, MAPT, andLRRK2 among the top association signals bothvalidates and extends our understanding of therole of these loci in determining susceptibilityfor PD (Table 1). In addition, these findingshighlight PD genetics as an example in whichpreviously known Mendelian loci or candidategenes anticipated the findings of GWA studies;more commonly, the genome-wide approachhas identified completely unexpected and novelsusceptibility genes. Two new putative PD-susceptibility loci, PARK16 and BST1, were alsodiscovered by these recent GWA studies. ThePARK16 locus, which was discovered in theJapanese PD cohort (rs947211, odds ratio =1.3, P = 1.5 × 10−12) (35) and independentlyvalidated in subjects of European ancestry (36),encompasses five genes—SLC45A3, NUCKS1,


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AR-JP: autosomalrecessive juvenileparkinsonism

RAB7L1, SLC41A1, and PM20D1—and futurework should aim to refine this association signalto identify the causal locus. The second novelPD gene, BST1, also demonstrated a significantassociation in the Japanese study (rs4538475,odds ratio = 1.2, P = 3.9 × 10−9) (35). Inter-estingly, this locus was not associated with PDsusceptibility in the European population; how-ever, a comparatively reduced allele frequencymay have limited statistical power for replica-tion (36). Little is known about the function ofBST1, but it appears to encode an enzyme thatcatalyzes the formation of cyclic ADP-ribose,which can regulate intracellular calcium stores(35). This hypothesis is potentially interestingbecause calcium dysregulation has previouslybeen implicated in mechanisms of dopaminer-gic cell loss in PD (104).

Despite the recent success, implementationof GWA in PD research remains behind thecurve compared with studies of other complexgenetic diseases, which have reported analysesinvolving tens of thousands of subjects. Similarlarge-scale collaborative efforts will be essen-tial to achieve the necessary statistical power todefine the full complement of common vari-ants, with an allele frequency >5%, that im-pact susceptibility for PD in the general popu-lation. As alluded to above, future GWA studiesin PD might additionally boost power throughassessment of prodromal nonmotor manifesta-tions or, alternatively, by leveraging the pre-cision of a neuropathologically defined pheno-type in autopsy cohorts. Ultimately, the adventof low-cost, full-genome sequencing will usherin the future of PD genetics, allowing full cata-loguing of both common and rare variants thateither cause or modify risk for disease.

Other Genetic Forms of Parkinsonism

In neurology diagnostic algorithms, lesionlocalization within the nervous system tradi-tionally takes precedence over specific etiology.Thus, a patient presenting with parkinsonismindicates a basal ganglia disorder, of whichPD is only one of many potential causes. Overthe past decade, a number of Mendelian forms

of parkinsonism have been enumerated withvariable degrees of clinical and pathologicaloverlap with PD (33, 38). This class of dis-orders is exemplified by autosomal recessivejuvenile parkinsonism (AR-JP), of which thebest-studied and most important cause is lossof function for parkin (PARK2). AR-JP wasinitially described in Japanese families witha chromosome 6 linkage signal, and in 1998,causative mutations were identified in parkin(105). This gene encodes a ubiquitously ex-pressed 465–amino acid protein with structuraland functional homology to ubiquitin ligases,which target cytoplasmic proteins for degrada-tion by the proteasome. The results of a largecase series suggest that parkin is a major causeof young-onset parkinsonism (106, 107). In 73families with an autosomal recessive inheri-tance pattern and at least one affected memberwith disease onset prior to age 45, nearly halfof the PD cases were due to parkin mutations(106). Further, in a cohort of 246 young-onset,sporadic cases, 15% were due to parkin, and thisfraction increased to 70% in the subset of caseswith onset before age 20 (107). In addition, thephenotype of parkin-associated disease, includ-ing both the typical motor manifestations andan excellent response to dopamine replacementtherapy, is often clinically indistinguishablefrom that of idiopathic PD.

By a number of criteria, however, parkin-associated AR-JP diverges from both idiopathicPD and the genetic forms of PD defined inthe preceding section, suggesting that it mayrepresent a distinct disease entity. First, themean age of onset for parkin disease (30 years)is substantially younger than for sporadic PD.Second, parkin often causes clinical featuresthat are atypical for PD, including symmetriconset of motor symptoms, early prominentdystonia, diurnal symptomatic fluctuations,reflex changes, and an overall slow and benigncourse of disease (108). Third, individuals withAR-JP due to parkin mutations do not appearto develop characteristic nonmotor manifesta-tions of PD, including loss of olfaction or latecognitive decline and dementia, suggesting amore restricted pathology (109). Finally, the


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PINK1: PTEN-induced kinase 1 gene

predominant neuropathology of parkin-associated disease at autopsy is bland ni-grostriatal degeneration, which consists ofdopaminergic cell loss in the SN in the absenceof LBs (110, 111), although LB pathology hasinfrequently been described (112, 113).

PTEN-induced kinase 1 (PINK1) is the sec-ond most common cause of AR-JP (114). Clin-ically, PINK1 (also known as PARK6) causes asyndrome similar to parkin-associated disease,and although in some cases it can be diffi-cult to distinguish from early-onset PD, atyp-ical features are often observed (115). PINK1encodes a widely expressed 581–amino acidserine-threonine kinase that is localized to mi-tochondria. No autopsies of PINK1 disease haveyet been reported. As detailed below, data fromanimal models suggest that PINK1 and Parkinproteins may function coordinately. DJ-1, alsoknown as PARK7, is a rare cause of AR-JP and,on the basis of the small number of clinical de-scriptions, appears to cause a similar syndromeas parkin and PINK1 (116). The pathology ofDJ-1 disease is also unknown. DJ-1 encodes aubiquitously expressed, conserved 189–aminoacid protein of still-uncertain function; how-ever, it has been reported to translocate to mi-tochondria in response to oxidative stress andmay thus participate in a protective response,together with the Parkin and PINK1 proteins(117).

Table 2 summarizes the parkinsonismgenes, including all of the currently validatedPARK loci (except for those already presentedin Table 1), and additionally includes examplesof some of the more diverse genetic disordersthat are also associated with significant parkin-sonism (37, 38). Due to space limitations, weare unable to discuss many of these genes inmore detail, and the table necessarily omits sev-eral other syndromes that, less frequently, cancause parkinsonism. Some of the disorders asso-ciated with the parkinsonism genes, such as AR-JP caused by parkin and PINK1, can be clinicallyindistinguishable from young-onset PD unlessatypical features emerge, genetic testing is pur-sued, or subjects eventually come to autopsy.In other cases, parkinsonism is a minor com-

ponent of a more heterogeneous neurologicalsyndrome or multisystem disorder that can bereadily differentiated from idiopathic PD (38).

On the basis of the clinical and pathologi-cal criteria outlined above, the disorders causedby the parkinsonism genes can be differenti-ated from idiopathic PD. Nevertheless, lessonsfrom the study of these syndromes are ap-plicable to our understanding of PD patho-genesis. An attractive hypothesis is that otherheritable parkinsonian disorders may provideinsights into mechanisms of dopaminergic cellvulnerability in the SN. Other data, such as(a) the finding that α-synuclein can be directlyubiquitinated by Parkin (118) or (b) evidencefor potential interactions in animal models (dis-cussed below) raise the possibility of an evenmore direct functional link between the mecha-nisms of PD and those of other genetic forms ofparkinsonism. In such a model, the parkinson-ism genes might additionally function as sus-ceptibility loci in idiopathic PD (33, 119). Thishypothesis has been most directly tested in thecase of the AR-JP genes, particularly parkin andPINK1. Interestingly, some asymptomatic het-erozygous carriers of parkin mutations showevidence of decreased striatal dopamine onnuclear imaging and, on careful examination,show signs of mild parkinsonism (112, 113,120). However, although these findings areconsistent with a haplo-insufficient, subclini-cal basal ganglionic disorder in some mutationcarriers, it has not yet been proven that theseindividuals progress to develop PD more fre-quently than the background population rate.In addition, association studies that evaluatedfor parkin or PINK1 mutations in sporadicPD cases versus controls have not consistentlyfound significant differences in carrier frequen-cies; however, these investigations have thusfar been relatively small and potentially under-powered (119, 121–123). Similarly, targeted ef-forts to identify more common polymorphismsin these genes have been equivocal (124, 125),and neither parkin nor PINK1 has been iden-tified among the most promising signals fromthe largest GWA studies performed to date (35,36). Therefore, although the preponderance of


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Table 2 Selected additional genetic causes of parkinsonism

Genea Chromosome Protein function Clinical phenotypeb Pathology Refs.parkin(PARK2)

6q25 E3 ubiquitin proteinligase

AR-JP, often indistinguishablefrom PD, but also with dystonia,reflex changes

Nigrostriataldegeneration, noinclusions

105

PINK1(PARK6)

1p36 Mitochondrial serine-threonine kinase

AR-JP, similar to parkin Unknown 114

DJ-1(PARK7)

1p36 Unknown, possiblerole in stress response

AR-JP, similar to parkin Unknown 116

ATP13A2(PARK9)

22q13 Lysosomal cationtransporter ATPase

Kufor-Rakeb disease (AR),parkinsonism and dementia

Unknown 163

FBXO7(PARK15)

22q12 E3 ubiquitin proteinligase

Pallido-pyramidal syndrome (AR),dystonia and parkinsonism

Unknown 164

PLA2G6(PARK14)

22q13 Phospholipase A2 NBIA-2 (AR), dystonia,parkinsonism, and dementia

Neuroaxonal dystrophy,iron accumulation

165

PANK2 20p13 Pantothenate kinase NBIA-1 (AR), dystonia,parkinsonism, and dementia

Neuroaxonal dystrophy,iron accumulation

166

ATP7B 13q14 Copper transporterATPase

Wilson’s disease (AR),parkinsonism, liver failure,neuropsychiatric symptoms

Basal ganglia copperaccumulation anddegeneration

167

GRN 17q21 Progranulin, growthfactor

Frontotemporal dementia (AD),dementia with or withoutparkinsonism

Ubiquitin/TDP-43inclusions

168,169

ATXN2(SCA2)

12q24 Unknown, enriched inGolgi apparatus

Spinocerebellar ataxia (AD), withor without parkinsonism

Polyglutamine-repeatnuclear inclusions

170

GCH1(DYT5)

14q22 GTP cyclohydrolase I,dopaminebiosynthesis

Dopa-responsive dystonia (AD),occasionally phenocopied byparkin

No nigral degeneration,no inclusions

171

aAll validated PARK loci are presented first, followed by selected causes of other heritable parkinsonian disorders. Of the PARK loci, the original reports ofpathogenicity for PARK5 (UCHL1) and PARK13 (Omi/HTR2) have been questioned, and these loci have not been independently replicated (33, 37).bAbbreviations: AD, autosomal dominant; AR, autosomal recessive; AR-JP, autosomal recessive juvenile parkinsonism; NBIA, neurodegeneration withbrain iron accumulation.

evidence does not yet support a major role forthe parkinsonism genes in increasing PD risk,larger studies will be necessary to definitivelyassess the possibility of more modest effects.

LESSONS FROM ANIMALMODELS OF PARKINSON’SDISEASE

Experimental animal models have been an im-portant part of PD research for many years.One widely used model is based on theaforementioned outbreak of MPTP-inducedparkinsonism in drug users (12). Subsequentwork demonstrated that the active metabolite

of MPTP, MPP+, poisons the electron-transport chain through inhibition of mito-chondrial complex I, leading to a selectiveloss of dopaminergic neurons. Recognition ofthe mechanisms of MPTP poisoning has mo-tivated many studies of mitochondrial func-tion in PD, a theme that has been reinforcedby recent studies of Parkin and PINK1, asdescribed below. Other toxins, including 6-hydroxydopamine (126), rotenone (127), andparaquat (128), can also produce relatively se-lective loss of dopaminergic neurons. Althoughtoxin-based models have been instrumental forthe study of mechanisms and consequences ofdopaminergic neuronal loss, their relevance to


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the mechanisms of pathogenesis in PD contin-ues to be debated.

Not surprisingly, genetic revelations inPD and related parkinsonian disorders havespurred the development of new animal mod-els. The initial key insight was the discovery ofSNCA mutations in familial PD and the findingthat α-synuclein is the major constituent ofLBs. Several groups attempted to model PD byoverexpressing wild-type and mutant versionsof human α-synuclein in model organismsbased on a postulated toxic gain-of-functionmechanism. In mice, transgenic expressionof wild-type human α-synuclein producesa reduction in striatal dopaminergic nerveterminals, concomitant decreased motor per-formance, and formation of α-synuclein-richneuronal cytoplasmic and nuclear inclusions(129). However, such mice do not display lossof dopamine neurons. Models based on overex-pression of α-synuclein that carry the disease-causing A53T mutation show marked aggrega-tion of α-synuclein in the brainstem and spinalcord, along with severe axonopathy and relatedmotor deficits (130, 131). Again, dopaminergicneurons are largely spared, despite substantialexpression of α-synuclein in the SN. Thus, lossof SN dopaminergic neurons, which constitutea clinically relevant cell population, has notbeen a striking feature of the α-synucleintransgenic mouse models developed to date.However, these models may still provide im-portant tools to explore the in vivo mechanismsregulating α-synuclein aggregation as well astoxicity to nondopaminergic cell populations,as occurs in PD and other α-synucleinopathies.

Nonetheless, because many of the clini-cally defining symptoms of PD derive fromloss of SN dopaminergic neurons, additionalstrategies for modeling α-synuclein aggrega-tion and neurotoxicity have been pursued. In-jection of adeno-associated virus that expresseswild-type or A53T mutant α-synuclein into ratSN produced a 30–80% loss of dopaminergicneurons within eight weeks (132), and simi-lar toxicity was observed with adeno-associatedvirus–mediated expression of A30P α-synuclein(133). Lentiviral-mediated expression of α-

synuclein also produced significant dopaminer-gic cell death in rats (134), mice (135), and non-human primates (136). Additionally, numerousα-synuclein-containing aggregates in neuronalcell bodies and neurites were observed follow-ing viral-mediated expression of α-synuclein inrat (132, 134). Interestingly, loss of SN neu-rons in this system was rescued by expressionof Parkin (137). Because inclusion body forma-tion and neurodegeneration are independentof parkin in α-synuclein transgenic mice (138),the findings in the rat viral transduction modelraise the intriguing possibility that dopamin-ergic neuron–specific interactions connect α-synuclein and Parkin mechanistically.

Given the power of simple model organismsto dissect fundamental biological pathways, anumber of groups have also modeled PD inmore tractable genetic systems. Expression ofhuman α-synuclein is toxic in yeast (139, 140),nematodes (141), and fruit flies (142). Manyof these models replicate key biochemical andcell biological features of PD. Expression ofwild-type or PD-linked mutant forms of hu-man α-synuclein in Drosophila leads to age-dependent degeneration of dopaminergic neu-rons, progressive locomotor dysfunction, andformation of α-synuclein-rich neuronal cyto-plasmic and neuritic aggregates that resembleauthentic LBs. Although mutant forms of α-synuclein were modestly more toxic than wild-type α-synuclein, overall similar effects wereobserved, which is consistent with a central rolefor α-synuclein in both familial and sporadicforms of the disorder, as suggested by humangenetic evidence.

Work in simple model organisms has alsocontributed substantially to our understandingof the relationship between α-synuclein ag-gregation and PD pathogenesis. Soon after thedevelopment of the α-synuclein transgenic flymodel of PD, expression of the human chaper-one protein HSP70 was reported to ameliorateneurotoxicity (143), which is consistent withthe hypothesis that abnormal protein foldingplays a key role in disease pathogenesis. Anumber of sequence motifs, including the cen-tral NAC region and both serine and tyrosine


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phosphorylation sites in the C terminus,influence the ability of α-synuclein to formfibrillar aggregates. Targeted mutagenesis ofthese sequences has provided strong evidencethat aggregation of α-synuclein is critical forneurotoxicity (144). Interestingly, however,dopaminergic cell loss appeared to correlatewith smaller oligomeric structures of α-synuclein rather than with higher-order fibrils(145, 146); therefore, larger macromolecularaggregates, including the LB, may serve aneuroprotective function by forming a sink forsmaller toxic species of α-synuclein. In comple-mentary experiments, a series of mutant formsof α-synuclein were assayed for their propensityto form oligomers and fibrils in vitro and weresubsequently evaluated for in vivo neurotoxi-city in the Drosophila and Caenorhabditis eleganssystems (147). These results also implicatedoligomeric species of α-synuclein as toxic,while suggesting that aggregation into higher-order fibrillar species is neuroprotective.Generally, experiments in mammalian modelsare also consistent with a role for aggregation inmediating α-synuclein neurotoxicity, althoughit is more challenging to single out a particularα-synuclein species as responsible (148, 149).

A number of laboratories have used the con-ventional loss-of-function approach in modelorganisms to investigate the biological rolesof genes that cause AR-JP. Mutations inDrosophila parkin cause prominent mitochon-drial pathology, including abnormal morphol-ogy and resultant cellular toxicity (150). A sim-ilar phenotype was subsequently observed inPINK1 mutant flies, and genetic epistasis ex-periments powerfully demonstrated that parkinand PINK1 act sequentially to regulate mito-chondrial function (151, 152). More recently,genetic manipulation of the well-conserved mi-tochondrial fission and fusion machinery wasfound to strongly interact with parkin andPINK1 mutants to modify cellular toxicity,which implicates these genes in the regulationof mitochondrial dynamics (153–155). Despitethese striking findings in Drosophila, mice lack-ing parkin and PINK1 individually, or togetherin double knockouts, fail to show dramatic

mitochondrial phenotypes or dopaminergic cellloss, even when DJ-1 is also removed (156).These observations suggest the possibility ofadditional functional redundancy in the murinesystem.

Because the genetic link between LRRK2and PD is a relatively recent one, less workhas been reported for animal models based onthe manipulation of LRRK2. However, recentexperiments in transgenic mice are consistentwith an association between gain-of-functionkinase activity and neurotoxicity (157). An in-triguing recent report suggests that increasedlevels of LRRK2 may enhance α-synuclein ag-gregation and neurotoxicity, whereas reduc-ing LRRK2 gene dosage suppresses α-synucleinneuropathology (158). These findings corre-late well with the presence of LB pathology inpatients with LRRK2-associated PD, and theymay provide an experimental system in which tofurther dissect the possible connection amongLRRK2 activity, α-synuclein aggregation, andsubsequent neurodegeneration.

A MODEL OF PARKINSON’SDISEASE PATHOGENESIS

Figure 6 presents a synthesis of our currentknowledge on the mechanisms of PD patho-genesis, with an emphasis on recent geneticdiscoveries. In our model, SNCA gene expres-sion and aggregation of α-synuclein proteinconstitute the central pathway that leads toneurotoxicity and neurodegeneration in PD.Although LB formation is the outcome ofthis cascade, it remains to be determinedwhich α-synuclein species is harmful, and assuggested above, several studies implicate anoligomeric form. SNCA mutations promot-ing fibrillation or increased gene expression,via rare locus multiplication or more commonpromoter polymorphisms, most directly trig-ger this toxic pathway. Other recently identi-fied PD-susceptibility genes, including LRRK2,GBA, and MAPT, probably influence thiscentral cascade, although understanding thedetailed mechanisms remains an importantgoal. The involvement of GBA implicates the


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MAPT

SNCA

Other genes

Nucleus

GBA

Lysosome

LRRK2

Toxic ?

?

parkinPINK1DJ-1

Oxidativestress

Tau

Mitochondrion

Lewy body

AgeEnvironment

Figure 6A model of Parkinson’s disease (PD) pathogenesis. Aggregation of α-synuclein is proposed as the centralpathway leading to neurotoxicity in PD. Other PD-susceptibility genes, including the microtubule-associated protein Tau gene (MAPT ), the glucocerebrosidase gene (GBA), and the leucine-rich repeat kinase2 gene (LRRK2), may participate in or modify the progression of this cascade in a still-undefined fashion.The pathway culminates with the formation of α-synuclein fibrils and deposition into Lewy bodies;however, α-synuclein oligomers may be the toxic species, although the mechanisms are still unknown.parkin, the PTEN-induced kinase 1 gene (PINK1), and DJ-1 may coordinately influence mitochondrialdynamics and the response to oxidative stress, thereby contributing to neuronal survival, particularly insubstantia nigra dopaminergic cells. The point of intersection between the α-synuclein cascade and theparkin/PINK1 pathway remains to be determined.


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lysosomal degradation machinery as potentiallyimportant, and the participation of Tau il-lustrates a possible link between PD and thepathogenesis of other neurodegenerative dis-eases, including Alzheimer’s disease and othertauopathies. In addition to genetic factors, ag-ing is a potent determinant of PD susceptibility,and additional environmental triggers proba-bly contribute. Some of these exogenous riskfactors, such as the potential role of pesticidesand toxins, may target mitochondria, leadingto the production of damaging reactive oxygenspecies. Finally, several parkinsonism genes,notably parkin, PINK1, and DJ-1, have beenfunctionally linked to mitochondria and havebeen proposed to mediate a protective cellu-lar response. A key question remains how di-rectly these genes interact with the central cas-cade of α-synuclein aggregation and toxicity inPD, or whether they alternatively constitute aparallel pathway that is important to neuronalhealth and survival, particularly for dopaminer-gic cells.

CODA: WHAT ISPARKINSON’S DISEASE?

Although PD was initially recognized and de-scribed as a purely clinical syndrome, recentprogress has splintered the unitary conceptionof this disease into a number of alternate views.Some have suggested embracing everythingthat behaves clinically as PD under a single di-agnostic umbrella. Others have argued in favorof abandoning PD as a single clinicopathologicentity, instead enumerating many subtypes onthe basis of varying clinical features, familial-ity, and autopsy findings. Although we acknowl-edge the cross currents that motivate these di-vergent approaches, we believe that a critical

survey of the field suggests an alternate tack.We propose that PD is a precisely definable anddistinct disease entity with a particular clinical,pathological, and genetic signature. Clinically,PD begins insidiously with a cluster of non-motor symptoms that anticipate the develop-ment of motor manifestations by many years,and late-stage disease nearly universally causescognitive decline and other disabling compli-cations. Pathologically, PD is characterized byα-synuclein pathology and neurodegenerationof a range of vulnerable cell types throughoutthe nervous system. Although LB formation inthe midbrain SN and associated dopaminergiccell loss remain the accepted pathologic criteriafor definitive diagnosis, they may develop rela-tively late in the overall disease course. Whereasthe manifestation of PD is strongly influencedby aging and possibly other environmental fac-tors, genetic susceptibility may be necessary forall cases, and a growing list of genetic variantsappear sufficient to cause disease in a substan-tial minority of cases, especially in certain ethnicpopulations. The notion of idiopathic or spo-radic PD needs to be reconsidered: All PD isprobably genetically influenced, although thenumber and identity of risk alleles vary fromcase to case (Figure 5). Finally, as with mostcomplex human phenotypes, there is substantialheterogeneity in PD presentations, and thereare also great mimics. At present, making thisdistinction may not always have a significantimpact on patient care. However, in the fore-seeable future, we anticipate that answering thequestion “What is PD?” will become routinein clinical practice, enabling us to identify pa-tients with either prodromal or increased sus-ceptibility for disease and to nominate them fortherapies targeting the central mechanisms ofpathogenesis.

SUMMARY POINTS

1. PD is clinically defined by the development of tremor, bradykinesia, rigidity, and posturalinstability, and it is also accompanied by a host of nonmotor manifestations, includingconstipation, urinary symptoms, sleep disorder, and dementia. A PD prodrome of non-motor features may precede the development of cardinal motor symptoms by many years.


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2. PD is pathologically defined by neurodegeneration of SN dopaminergic cells in associ-ation with α-synuclein pathology; however, Lewy pathology is additionally manifestedin vulnerable cell populations throughout the peripheral and central nervous systems.

3. Several PD-susceptibility genes have been validated, and the identified genetic variantsdefine a broad spectrum of disease risk, blurring the distinction between familial andsporadic disease. Some genes, including SNCA and LRRK2, harbor rare, highly penetrantMendelian alleles in addition to common polymorphisms that have a more modest effecton disease susceptibility.

4. The discovery of other genetic causes of parkinsonism, including parkin, PINK1, andDJ-1, has defined an important cellular response pathway for oxidative stress that maypartly explain the relatively selective vulnerability of SN dopaminergic cells in PD.

5. Genetic advances in PD and related disorders have spurred the development of improvedanimal models and have defined the core mechanisms underlying the disease. The ag-gregation of α-synuclein probably comprises a central cascade that leads to neurotoxicityand neurodegeneration.

DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings thatmight be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

We apologize to our colleagues whose work we were unable to discuss or cite due to spacelimitations. J.M.S. is supported by the National Institutes of Health (NIH) and by the ClinicalInvestigator Training Program: Beth Israel Deaconess Medical Center–Harvard-MIT HealthSciences and Technology Division, in collaboration with Pfizer, Inc. and Merck & Co. BothP.D.J. and M.B.F. are supported by the NIH, and M.B.F. also receives support from the AmericanParkinson’s Disease Association.

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154. Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, et al. 2008. The PINK1/parkinpathway regulates mitochondrial morphology. Proc. Natl. Acad. Sci. USA 105:1638–43

155. Yang Y, Ouyang Y, Yang L, Beal MF, McQuibban A, et al. 2008. Pink1 regulates mitochondrial dynamicsthrough interaction with the fission/fusion machinery. Proc. Natl. Acad. Sci. USA 105:7070–75

156. Kitada T, Tong Y, Gautier CA, Shen J. 2009. Absence of nigral degeneration in aged parkin/DJ-1/PINK1triple knockout mice. J. Neurochem. 111:696–702

157. MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, et al. 2006. The familial parkinsonism geneLRRK2 regulates neurite process morphology. Neuron 52:587–93

158. Lin X, Parisiadou L, Gu X-L, Wang L, Shim H, et al. 2009. Leucine-rich repeat kinase 2 regulatesthe progression of neuropathology induced by Parkinson’s-disease-related mutant α-synuclein. Neuron64:807–27

159. Hicks AA, Petursson H, Jonsson T, Stefansson H, Johannsdottir HS, et al. 2002. A susceptibility genefor late-onset idiopathic Parkinson’s disease. Ann. Neurol. 52:549–55

160. Pankratz N, Nichols WC, Uniacke SK, Halter C, Rudolph A, et al. 2003. Significant linkage of Parkinsondisease to chromosome 2q36–37. Am. J. Hum. Genet. 72:1053–57

161. Pankratz N, Nichols WC, Uniacke SK, Halter C, Murrell J, et al. 2003. Genome-wide linkage analysisand evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum.Mol. Genet. 12:2599–608

162. Gasser T, Muller-Myhsok B, Wszolek ZK, Oehlmann R, Calne DB, et al. 1998. A susceptibility locusfor Parkinson’s disease maps to chromosome 2p13. Nat. Genet. 18:262–65

163. Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, et al. 2006. Hereditary parkinsonismwith dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat.Genet. 38:1184–91

164. Shojaee S, Sina F, Banihosseini SS, Kazemi MH, Kalhor R, et al. 2008. Genome-wide linkage analysisof a Parkinsonian-pyramidal syndrome pedigree by 500 K SNP arrays. Am. J. Hum. Genet. 82:1375–84

165. Morgan NV, Westaway SK, Morton JEV, Gregory A, Gissen P, et al. 2006. PLA2G6, encoding aphospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat. Genet. 38:752–54

166. Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, et al. 2001. A novel pantothenate kinasegene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat. Genet. 28:345–49

167. Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. 1993. The Wilson disease gene is a putativecopper transporting P-type ATPase similar to the Menkes gene. Nat. Genet. 5:327–37

168. Baker M, Mackenzie I, Pickering-Brown S, Gass J, Rademakers R, et al. 2006. Mutations in progranulincause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–19

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NOTE ADDED IN PROOF

After this review went to press, another large and important PD GWAS study (see below) waspublished. This study confirmed the previously known associations at the SNCA and MAPT lociand identified two additional loci with genome-wide significant associations, including GAK andHLA-DRA. Suggestive association between the GAK locus and PD was previously detected byanother study (55).

Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, et al. 2010. Common ge-netic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease.Nat. Genet. 42:781–85


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PM06-FrontMatter ARI 1 December 2010 11:14

Annual Review ofPathology:Mechanisms ofDisease

Volume 6, 2011Contents

Starting in Immunology by Way of ImmunopathologyEmil R. Unanue � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

The Pathogenesis of SepsisDeborah J. Stearns-Kurosawa, Marcin F. Osuchowski, Catherine Valentine,

Shinichiro Kurosawa, and Daniel G. Remick � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �19

EGFR Mutations and Lung CancerGilda da Cunha Santos, Frances A. Shepherd, and Ming Sound Tsao � � � � � � � � � � � � � � � � � � � �49

Zebrafish Models for CancerShu Liu and Steven D. Leach � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �71

Mouse Models of CancerDong-Joo Cheon and Sandra Orsulic � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �95

Disorders of Bone RemodelingXu Feng and Jay M. McDonald � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 121

The Acute Respiratory Distress Syndrome: Pathogenesisand TreatmentMichael A. Matthay and Rachel L. Zemans � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 147

The HIF Pathway and ErythrocytosisFrank S. Lee and Melanie J. Percy � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 165

Parkinson’s Disease: Genetics and PathogenesisJoshua M. Shulman, Philip L. De Jager, and Mel B. Feany � � � � � � � � � � � � � � � � � � � � � � � � � � � � 193

Pathogenic Mechanisms of HIV DiseaseSusan Moir, Tae-Wook Chun, and Anthony S. Fauci � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 223

Pathogenesis of MyelomaKenneth C. Anderson and Ruben D. Carrasco � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 249

Alternative Macrophage Activation and MetabolismJustin I. Odegaard and Ajay Chawla � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 275

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The Pathobiology of Arrhythmogenic CardiomyopathyJeffrey E. Saffitz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 299

Mechanisms of Leukocyte Transendothelial MigrationWilliam A. Muller � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 323

Retinoids, Retinoic Acid Receptors, and CancerXiao-Han Tang and Lorraine J. Gudas � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 345

Biomedical Differences Between Human and Nonhuman Hominids:Potential Roles for Uniquely Human Aspects of Sialic Acid BiologyNissi M. Varki, Elizabeth Strobert, Edward J. Dick Jr., Kurt Benirschke,

and Ajit Varki � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 365

A Glimpse of Various Pathogenetic Mechanismsof Diabetic NephropathyYashpal S. Kanwar, Lin Sun, Ping Xie, Fu-you Liu, and Sheldon Chen � � � � � � � � � � � � � � � 395

Pathogenesis of Liver FibrosisVirginia Hernandez-Gea and Scott L. Friedman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 425

Mesenchymal Stem Cells: Mechanisms of InflammationNora G. Singer and Arnold I. Caplan � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 457

Molecular Genetics of Colorectal CancerEric R. Fearon � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 479

The Pathogenesis of Systemic SclerosisTamiko R. Katsumoto, Michael L. Whitfield, and M. Kari Connolly � � � � � � � � � � � � � � � � � � � 509

Indexes

Cumulative Index of Contributing Authors, Volumes 1–6 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 539

Cumulative Index of Chapter Titles, Volumes 1–6 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 542

Errata

An online log of corrections to Annual Review of Pathology: Mechanisms of Disease articlesmay be found at http://pathol.annualreviews.org

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parkinson's disease: genetics and pathogenesis

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