Pathogenesis of Parkinson's disease

Pathogenesis of Parkinson’s Disease

Etienne C. Hirsch, PhD,1,2,3 Peter Jenner, PhD, DSc, FRPharmS,4 and Serge Przedborski, MD, PhD5*

1Universit�e Pierre et Marie Curie–Paris 06, Centre de Recherche de l’Institut du Cerveau et de la Mo€elle Epiniere,

Hopital de la Salpetriere, Paris, France2Institut National de la Sant�e et de la Recherche M�edicale, Unit�e Mixte de Recherche U975, Paris, France

3Centre National de la Recherche Scientifique, Unit�e Mixte de Recherche 7225, Paris, France4Neurodegenerative Diseases Research Centre, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King’s College,

London, United Kingdom5Department of Neurology, Department of Pathology and Cell Biology, and the Center for Motor Neuron Biology and Disease,

Columbia University, New York, New York

ABSTRACT: Parkinson’s disease is a commonadult-onset neurodegenerative disorder whose pathoge-nesis remains essentially unknown. Currently, it is believedthat the neurodegenerative process in Parkinson’s diseaseis a combination of both cell-autonomous and non-cell-au-tonomous mechanisms. Proposed cell-autonomousmechanisms include alterations in mitochondrial bioener-getics, dysregulation of calcium homeostasis, andimpaired turnover of mitochondria. As for the proposednon-cell-autonomous mechanisms, they involve prion-like

behavior of misfolded proteins and neuroinflammation.This suggests that cell death in Parkinson’s disease iscaused by a multifactorial cascade of pathogenic eventsand argues that effective neuroprotective therapy for Par-kinson’s disease may have to rely on multiple drug interven-tions.VC 2012 Movement Disorder Society

Key Words: Dopamine neuron, inflammation, neuro-degeneration, mitochndria, misfolded protein

Parkinson’s disease (PD) is a common adult-onsetneurodegenerative disease characterized by the rela-tively selective death of neuronal subtypes, notablythose of the nigrostriatal dopaminergic pathway.1 PDis usually characterized by the changes that occur inmotor function, such as bradykinesia, rigidity, pos-tural instability, and rest tremor, although myriad

nonmotor manifestations are increasingly recognized.2

PD, like many of the prominent adult-onset neurode-generative disorders such as Alzheimer’s disease andamyotrophic lateral sclerosis, is primarily sporadic,

that is, it occurs in the absence of any obvious genetic

linkage.1 However, in rare instances, PD is inherited,

and in these cases, the PD phenotype is transmitted ei-

ther as a recessive or dominant trait.1 Yet the motor

phenotypes of both the sporadic and familial forms of

PD are almost identical, implying that they might

share common underlying mechanisms. Perhaps not

surprisingly, many researchers argue that this pheno-

typic similarity justifies the intense analyses of rare

genetic forms of PD, as these studies could well illumi-

nate the pathogenesis of both sporadic and inherited

disease. Moreover, the familial forms of PD do not

occur because of mutations in a single gene but result

from mutations in multiple distinct genes.3 This

genetic heterogeneity is to be expected because as dis-

cussed elsewhere,4 the taxonomy of neurodegenerative

disorders rests on clinical, biochemical, and neuro-

pathological criteria that serve to lump together ill-

nesses that simply look alike. From a pathogenic point

------------------------------------------------------------*Correspondence to: Serge Przedborski, Center for Motor NeuronBiology and Disease, P&S 5-420, Columbia University, 630 West 168thStreet, New York, NY 10032; [email protected]

Relevant conflicts of interest/financial disclosures: The authors aresupported by grants from the National Institutes of Health (NS042269,NS064191, NS38370, NS070276, and NS072182 to S.P.), the U.S.Department of Defense (W81XWH-08-1-0522, W81XWH-08-1-0465, andW81XWH-09-1-0245 to S.P.), the Parkinson Disease Foundation, theThomas Hartman Foundation For Parkinson’s Research, Project A.L.S,the Wings-over-Wall Street/Muscular Dystrophy Association. INSERM,CNRS, Universit�e Pierre et Marie Curie, Cure Parkinson Foundation,Rosetrees Trust, Parkinson UK, and National Parkinson Foundation,Centre national de la recherche scientifique, Institut national de la sant�eet de la recherche m�edicale.Full financial disclosures and author roles may be found in the onlineversion of this article.

Received: 9 January 2012; Revised: 3 April 2012; Accepted: 8 April2012Published online in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/mds.25032

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of view, it is possible that the apparent convergence ofthe clinical PD phenotype caused by different genestells us that the actions of the mutated forms intersectin common pathways. In this regard, we believe thatdespite the genotypic diversity of familial PD, insightsinto its pathogenesis that have been gained in the lastdecade have begun to reveal some new and interestingthemes, one of which has already started to challengeour traditional focus on neurons. Indeed, it is increas-ingly recognized that degenerating neurons in PD,such as dopaminergic neurons of the nigrostriatalpathway, do not live in isolation. These neuronsreceive a variety of afferents and are surrounded by alarge number of nondopaminergic neurons likeGABAergic and cholinergic neurons and nonneuronalcells such as astrocytes and microglia. Thus, it is thecurrent belief that the neurodegeneration in PD occursin response to a mixture of deleterious mechanismstaking place both inside the degenerating neurons (ie,cell-autonomous processes) and outside the degenerat-ing neurons (ie, non-cell-autonomous processes). Wenow explore this convenient division of cellular andmolecular events occurring in PD to discuss some ofthe most recent concepts on its pathogenesis.

Cell-Autonomous Mechanisms

Cell-autonomous mechanisms in PD include oxida-tive stress, protein aggregation, defects in the ubiqui-tin-proteasome pathway, and autophagy, but in ouropinion it is alterations in mitochondrial function thathave gained prominence.4 Over the past decade, therehas been an explosion of new information on the neu-robiology of PD due in part to major advances in mo-lecular genetics.5 Since the early 2000s, the number ofmutations in apparently disparate genes identified inPD families has increased exponentially. Importantly,at least 3 of the products encoded by these genes,namely, DJ-1, Parkin, and PINK1, have been con-nected to mitochondria.4 LRRK2 might also plays arole in modulating the response to mitochondrial inhi-bition, and mutations in LRRK2 might enhance thesusceptibility of dopaminergic neurons to other insultsoccurring in PD.6 Furthermore, in sporadic PD, laser-capture microdissection showed high levels of deletedmitochondrial DNA in individual dopaminergic neu-rons in the substantia nigra.7 The level of mitochon-drial DNA deletion was greater in cytochrome coxidase-deficient neurons than in neurons with normalcytochrome c oxidase activity.7 This supports the ideathat the observed somatic mitochondrial DNAmutations cause functional defects in mitochondrialrespiration in nigral dopaminergic neurons. Collec-tively, these findings in familial and sporadic PDprompted revisiting the nature of the mitochondrial

defect in PD, and this has led to at least 3 recentbreakthroughs.

The Return of Bioenergetics

For years, bioinformatics on small PD cohorts hasbeen used to try to gain insights into both the etiologyand pathogenesis of PD, but with little success. In arecent colossal collaborative effort, genomic materialfrom around the world was combined to perform agenome-wide meta-analysis of gene sets in 410 sam-ples from patients with symptomatic and presympto-matic PD and normal controls.8 The study analyzed6.8 million raw data points from 9 genome-wideexpression studies, and 185 laser-captured human do-paminergic neuron and substantia nigra transcrip-tomes.8 This massive amount of data and analyses ledto the identification of a strong association betweenPD and 10 molecular pathways all related to bioener-getics, including glucose metabolism and mitochon-drial oxidative phosphorylation.8 Expression of manyof the genes governing mitochondrial bioenergeticsand oxidative metabolism is modulated by the tran-scriptional coactivator PGC-1a, and in PGC-1a-knockout mice, expression of the genes responsible formitochondrial respiration is reduced and mitochon-drial respiration decreased.9 Not surprisingly, theauthors inferred from their findings that PGC-1a regu-lation is perturbed in PD (Fig. 1).

Yet a key question is left unanswered: how doesPGC1a become dysregulated in PD? Perhaps a begin-ning of the explanation can be found in the work ofShin et al10 on a new Parkin-interacting substratecalled PARIS. The latter is degraded by a Parkin-de-pendent mechanism and represses the expression ofPGC1a, among other targets.10 Collectively, thesedata allow us to propose the following novel patho-genic scenario of PD. Following a loss of Parkin func-tion, because of either genetic mutations orposttranslational modifications such as oxidativestress, PARIS accumulates and represses PGC1a,which, in turn, leads to the downregulation of all thePGC1a-responsive genes, including those regulatingglucose metabolism and mitochondrial respiration,hence provoking a defect in bioenergetics and ulti-mately neuronal degeneration (Fig. 1).

Altered Calcium Conductance

In other recent studies, highly susceptible nigral do-paminergic neurons were shown to exhibit electro-physiological characteristics distinct from those of themore resistant ventral tegmental dopaminergic neu-rons.11,12 The study by Chan and collaborators11

showed that nigral neurons rely on L-type Cav1.3 cal-cium channels to drive their rhythmic pacemaking ac-tivity, which is associated with greater calcium

H I R S C H E T A L .

2 Movement Disorders, Vol. 000, No. 000, 0000

conductance compared to ventral tegmental dopami-nergic neurons. In the subsequent study by Guzmanand collaborators,12 it was shown that the greater cal-cium conductance in nigral dopaminergic neurons isassociated with increased intramitochondrial produc-tion of reactive oxygen species (ROS). However, wedo not believe the principles of mitochondrial bioener-getics invoked by the authors to explain how increasedintracellular calcium concentration causes increasedmitochondrial ROS production are correct. Indeed,bioenergetic principles argue that the faster the elec-tron flow through the electron transport chain, theshorter the time the ubiquinone complex is reducedand the fewer electrons passed to molecular oxygen.Accordingly, the harder the mitochondria work, theless (and not the more) ROS is produced. Thus,should the ROS data be confirmed, the basis betweencalcium dyshomeostasis and intramitochondrial ROSproduction may lie in some other explanation. None-theless, even if we disagree with the authors’ interpre-tation of their data, it remains true that this workshows that the singular calcium-dependent pacemak-ing of nigral neurons is associated with increased mi-tochondrial ROS.12 If confirmed, the latter findings

may represent one of the molecular underpinnings ofthe reported heightened mitochondrial DNA damagein nigral neurons in PD.7

Parkin and PINK1 Modulate Mitophagy

A third set of investigations brought the conceptthat PD pathogenesis might be linked to a defect inmitochondrial quality-control mechanisms. Althoughthese have only begun to be recognized in mammals,it is well established in yeast that when mitochondriaare defective, specific molecular machinery recognizesand then disposes of these damaged mitochondriathrough macroautophagy.4 This quality-control mech-anism maintains a healthy pool of mitochondria, andthe cell can then withstand the high energy demand ofneurons.4 Several groups, including our own, havedemonstrated that cytoplasmic Parkin can relocate tothe mitochondria following loss of mitochondrialmembrane potential,13–17 a well-known indicator ofmitochondrial dysfunction. Parkin translocation isPINK1 dependent,13–17 that is, in the absence ofPINK1, Parkin does not translocate to the mitochon-dria, even if the membrane potential is lost. Once mi-tochondria are decorated with Parkin, individual

FIG. 1. A scheme illustrating that cell death in Parkinson’s disease is a result of a multifactorial cascade of pathogenic events combining cell-auton-omous and non-cell-autonomous mechanisms. The cell-autonomous mechanisms shown include alterations in mitochondrial bioenergetics, dysre-gulation of calcium homeostasis, and impaired turnover of mitochondria. Many of the genes governing mitochondrial bioenergetics and oxidativemetabolism are modulated by the transcriptional coactivator PGC-1a, which is dysregulated in Parkinson’s disease, possibly because of the accu-mulation of a Parkin-interacting substrate called PARIS. The proposed non-cell-autonomous mechanisms involve prion-like behavior of misfoldedproteins and neuroinflammation. These combine to initiate neuronal cell death and propagate its progression. The combination illustrates that it isunlikely that pathogenesis in Parkinson’s disease can be stopped or slowed through any single therapeutic intervention.

P A T H O G E N E S I S O F P A R K I N S O N ’ S D I S E A S E


mitochondria quickly form clusters that migrate to theperinuclear region of the cell.14,17 There, these Parkin-decorated mitochondria colocalize with markers oflysosomes,14,17 suggesting that the mitochondrial clus-ters are degraded by macroautophagy. However, con-trary to events in yeast, we have recently challengedthe idea that Parkin/PINK1 is part of the machinery ofmacroautophagy degrading dysfunctional mitochon-dria. Instead, based on our findings,18 we propose thatParkin and PINK1 collaborate to merely facilitatedamaged mitochondria to be preferentially, but notexclusively, degraded by general macroautophagy.Nonetheless, whatever the actual molecular processinvolved, PD mutations in either Parkin or PINK1appear to hamper the normal turnover of damagedmitochondria.14,17 Thus, from the above studies, aloss of function of Parkin or PINK1 might preventdamaged mitochondria from being effectively elimi-nated, and this, in turn, may lead to neuronal dysfunc-tion and, ultimately, to even neuronal death (seeConclusions for further discussion on this theme). Inaddition, it has been reported that LRRK2 might regu-late autophagy/lysosomal function,19 but whether thisinvolves mitophagic pathways in the same way as Par-kin or PINK1 remains to be established (Fig. 1).

Non-Cell-Autonomous Mechanisms

Diffusion of Parkinson’s Disease over Timeand across Brain Regions

Although the symptoms of PD worsen over time,the mechanisms underlying the progression of the dis-ease across different brain regions are not fully under-stood. However, they very likely involve cellularinteractions known as non-cell-autonomous mecha-nisms. These mechanisms include a spreading of thepathology (especially of a-synuclein), a progressivedegeneration of dopaminergic and nondopaminergicneurons and inflammatory processes.

Lewy bodies and Lewy neurites composed of a-syn-uclein deposits are found in the substantia nigra parscompacta, where melanized neurons degenerate.20,21

Importantly, these also are present in nondopaminer-gic brain nuclei that die in PD and even in the periph-ery.20,21 From analyzing a series of brains at autopsy,Braak and coworkers22 suggested that a-synucleindeposition follows a stereotyped progression acrossthe nervous system. According to Braak’s view, thepathology would start during the preclinical phase ofPD at 2 independent loci, namely, the medulla oblon-gata and the olfactory structures. Because at this stagethere is no pathology in the substantia nigra, itremains to be established whether these cases, calledthe preclinical phase of PD or PD stage I, are truly apreclinical form of PD. In the early clinical stages ofPD, inclusions are found in the substantia nigra and

the midbrain and rapidly thereafter in the basal fore-brain, the basal ganglia, and the mesocortex. In theend stage of the disease, the inclusions invade thewhole neocortex. Yet the distribution of abnormal a-synuclein deposits does not correlate with disease du-ration and does not explain the progression of clinicalseverity of the disease.23 Furthermore, whether thosea-synuclein deposits truly herald neurodegeneration isstill unknown.

A role for a-synuclein in the progressive nature ofthe disease has been revitalized by the discovery of a-synuclein-immunoreactive Lewy bodies in embryonicgrafted cells in the striata of patients with PD.24,25

This suggests that pathology could spread from onecell to another and that a-synuclein could be trans-ferred from an affected neuron to a previously healthyneuron by a ‘‘prion-like’’ process. Subsequently,numerous investigators tried to substantiate this hy-pothesis using in vitro and in vivo approaches (for areview, see reference 26). Germane to this new con-cept are the following 3 observations. First, it hasbeen demonstrated that a-synuclein is present in thesecretory vesicles of neurons and various biologicalfluids, suggesting it might be secreted by exocytosis.26

Second, it has been found that exosomes from neuro-blastoma cell lines appear to be able to cargo the pro-tein from one cell to another.27 And third, it has beenshown that preformed fibrils generated from full-length and truncated recombinant a-synuclein enterprimary neurons, probably by adsorptive-mediatedendocytosis, and promote recruitment of soluble en-dogenous a-synuclein into insoluble inclusions reminis-cent of Lewy bodies.28 In the latter study, the authorsdemonstrated that the accumulation of pathologic a-synuclein led to decreases in synaptic proteins, pro-gressive impairments in neuronal excitability and con-nectivity, and, eventually, neuron death.28

Cell-to-cell transfer of a-synuclein can explain theformation of Lewy bodies and Lewy neurites butclearly does not account for the full spectrum of PDand especially not for the degeneration of all neurons.Indeed, neuronal loss in PD is not restricted to thesubstantia nigra or to neurons containing Lewybodies. Other neuronal populations also degeneratesuch as cholinergic neurons in the basal forebrain andthe midbrain tegmentum, serotonergic neurons in theraphe nuclei, noradrenergic neurons in the locuscoeruleus (for a review, see reference 29), and evenpyramidal neurons involved in corticocortical connec-tivity in the pre–supplementary motor area of the cere-bral cortex.30 The pathogenic mechanisms takingplace have scarcely been investigated and are pre-sumed to reflect events in the substantia nigra. Inter-estingly, the degeneration of some neurons might alsoinvolve non-cell-autonomous mechanisms. Indeed, acorrelation exists between the degree of neuronal



degeneration in the substantia nigra pars compactaand in the pedunculopontine nucleus (PPN),31,32

which sends cholinergic projections directly to nigraldopaminergic neurons. Interestingly, Toulorge and co-workers reported that the cholinergic agonist nicotinecan protect dopaminergic neurons in an in vitro modelof spontaneous and selective degeneration.33 However,protection only occurred when cytosolic calcium wasincreased. This rise in calcium was necessary to sensi-tize dopamine neurons to the action of nicotinethrough a mechanism involving a-bungarotoxin-sensi-tive (presumably a7) nicotinic acetylcholine receptorsand secondarily T-type voltage-gated calcium channels(Fig. 1). Thus, the degeneration of PPN cholinergicneurons in PD might exacerbate the loss of nigral do-paminergic neurons by reducing their stimulatoryinputs. Very similar findings have been made on therole of noradrenergic input to the substantia nigra andits effect on dopaminergic cell death. Yet other mecha-nisms such as loss of trophic support might alsoexplain neuronal loss in PD. In keeping with this,decreased concentrations of brain-derived neurotro-phic factor and nerve growth factor have beendescribed in the substantia nigra in PD34 whereas glialcell line–derived neurotrophic factor levels wereunchanged.35 Clearly, at this point further studies areneeded to determine if the changes in neurotrophicfactor levels are primary in neuronal degeneration inPD or merely represent a consequence of neuronaldysfunction.

Neuroinflammation—Instrumental inNeurodegeneration?

Interactions between neurons and nonneuronal cellsalso participate in the cascade of events leading toneurodegeneration in PD (Fig. 1). Indeed, astrocytosis,microgliosis, and even lymphocyte infiltration arefound in the substantia nigra in postmortem studies inPD (for a review, see references 36 and 37). In linewith this, levels of proinflammatory cytokines areincreased in the substantia, the striatum, and the cere-brospinal fluid of patients with PD.38 Perhaps impor-tantly, LRRK2 has been found to localize to activatedmicroglial cells, and the R1441G mutation enhancesthe release of cytokines from activated microglia andincreases cell death.39,40 This indicates that bothinnate and adaptive immunity are involved in thepathogenesis of PD. However, postmortem studies donot allow the determination of whether neuroinflam-mation participates in neuronal degeneration ormerely represents a consequence of it. To address thisissue, changes occurring in animal models of PD havebeen investigated along with the effects of interferingwith such mechanisms on the extent and time courseof neuronal loss.

Innate immunity has been studied following initia-tion of nigral dopaminergic cell loss produced by thesystemic injection of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).1

MPTP treatment resulted in extensive microglial acti-vation in both mice41 and nonhuman primates.42 Fur-thermore, reduction of microglial activation bycyclooxygenase-2 inhibitors,43 peroxisome prolifera-tor-activated receptor-gamma agonists,44 or tumor ne-crosis factor alpha manipulation45 reduced neuronaldegeneration. Microglial activation was also reportedin rats after viral vector–targeted overexpression ofhuman a-synuclein in midbrain dopamine neurons.46

Importantly, in vitro studies even suggested that a-syn-uclein deposition and inflammatory change potentiateeach other’s pathogenic activity and participate in theprogressive nature of neurodegeneration.47 Yet there isstill a debate about whether microglial activation isharmful. Indeed, microglial cells also produce anti-inflammatory cytokines and exert phagocytic activitiesthat could prevent the extension of neuronal degenera-tion. In this context, trying to switch the phenotype ofmicroglial cells from a proinflammatory M1 to animmunomodulatory M2 phenotype might represent aninteresting therapeutic strategy.48

Experimental studies have also shown that adaptiveimmunity is involved in animal models of PD (Fig. 1).T lymphocytes (CD4 and CD8 lymphocytes) but not Blymphocytes infiltrate the substantia nigra and thestriatum of MPTP-intoxicated mice.49–51 In thismodel, ablation of CD4 but not of CD8 lymphocytesprovided protection against MPTP toxicity to dopami-nergic neurons by a Fas/Fas ligand-mediated pathway.The specific antigens that trigger the lymphocyticresponse have not been identified but are likely includenitrated a-synuclein released from dying neurons.52,53

Conclusions

The growing consensus in PD research is that thedemise of selective subsets of neurons that characterizethis adult-onset neurodegenerative disorder resultsfrom a combination of cell-autonomous mechanisms(that is, mechanisms that take place inside dying neu-rons) and non-cell-autonomous mechanisms (that is,mechanisms that originate from outside the dying neu-rons). It is also important to stress that although thelion’s share of attention is given to dopaminergic neu-rons, many other neuronal subtypes degenerate in PD.There is as yet no evidence that different neuronalpopulations die by distinct pathogenic mechanisms, socurrently studying dopaminergic neurons is perfectlyappropriate, but this may need to be reviewed onceevents occurring outside the substantia nigra havereceived similar attention.



Among the cell-autonomous mechanisms, there is aresurgence of interest in the idea that mitochondrialdysfunction may be a key pathogenic mechanism ofPD. However, all recent studies have pointed towarddamaged mitochondria in PD occurring as a conse-quence of upstream molecular defects and not, as wasthought for many years, as a primary pathogenicevent. Significantly, above we discussed some of suchpotential primary defects that may lead to the accu-mulation of dysfunctional mitochondria in dopaminer-gic neurons, either because of enhanced damage or ofdecreased elimination, or both. Based on the newbody of information discussed here, the followingpathogenic scenario of PD emerges. In dopaminergicneurons, increased calcium conductance and the ensu-ing greater mitochondrial ROS production lead tohigher levels of damaged mitochondria. In normalindividuals, Parkin and PINK1 function to eliminatedamaged mitochondria by macroautophagy allowingnigral dopaminergic neurons to retain a normal poolof healthy mitochondria. In contrast, in PD a loss ofParkin function leads to a progressive buildup of dam-aged mitochondria because of a concerted effect toreduce PGC1a activity and a defect in Parkin/PINK1-dependent mitochondrial turnover. Thus, over time,the burden caused by mitochondrial dysfunction willrise and eventually reach a pathological threshold,provoking neuronal dysfunction and ultimately celldeath.

To this equation must be added the contribution ofnon-cell-autonomous mechanisms. In aggregate, thedata reviewed here on non-cell-autonomous mecha-nisms of neuronal degeneration in PD indicate ourvision of the disease involving only nigral dopaminer-gic neurons was much too simplistic. It is now wellestablished that the disease expands overtime to otherneuronal populations and that nonneuronal cells par-ticipate in this propagation. The consequences of thesecomplex cell interactions are that the pathophysiologyof the disease needs to be revisited in a cell-specificmanner. Indeed, a modified expression of a gene orprotein might have different consequences in differentcell types. This has recently been exemplified for theanti-inflammatory action of glucocorticoids. Indeed,stimulation of glucocorticoid receptors on microglialcells is neuroprotective in MPTP-intoxicated mice, butthis is not the case for the stimulation of glucocorti-coid receptors on dopaminergic neurons.54 These cell-specific properties will render any therapeutic interven-tion extremely difficult because the pharmacologicalagents will not only have to cross the blood–brain bar-rier but also to reach a specific cell type.

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Pathogenesis of Parkinson's disease