Recent advances in our understanding of Parkinson's disease

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Drug Discovery Today: Disease Mechanisms

DRUG DISCOVERY

TODAY

Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA

DISEASE Nervous system MECHANISMS

Recent advances in our understanding of Parkinson’s disease Seong Who Kim1,4, Han Seok Ko1, Valina L. Dawson1,2,3, Ted M. Dawson1,2,* 1 Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, 733 North Broadway Street, Suite 731, Baltimore, MD 21205, USA 2 Institute for Cell Engineering, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 3 Institute for Cell Engineering, Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 4 Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, South Korea

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disease with complex causes. Through scientific investigation of the gene products identified to be linked to inherited PD, common potential mechanisms in the development of PD are being unveiled, that is, defects in mitochondrial function as well as protein folding and degradation through the ubiquitin–proteosomal system leading to cell death. Understanding these mechanisms might lead to new arenas of therapeutic intervention. Introduction Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disease affecting 1% of the population by the age of 65 and 4–5% of the population by the age of 85. The well-known pathology of PD is the preferential death of dopaminergic neuron in substantia nigra pars compact (SNpc), causing a decrease in striatal dopamine (DA). It is characterized by motor abnormalities such as tremor, rigidity, slowness and postural instability. Several patients also suffer from depression, anxiety, autonomic disturbance and dementia [1]. The underlying cause of the DA cell death or the mechanism by which these cells degenerate remains elusive and no preventive treatment is available (Fig. 1). Through investigations on the properties of the gene products in familial PD, there have been tremendous advances in our understandings of the PD, suggesting that defects in *Corresponding author: T.M. Dawson ([email protected]) 1740-6765/$ ß 2005 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ddmec.2005.11.015

Section Editors: Andrey Mazarati – Department of Pediatrics, UCLA, USA Claude Wasterlain – Department of Cardiology, UCLA, USA mitochondrial function, as well as alterations in protein folding and degradation through the ubiquitin–proteosomal system (UPS), play prominent roles in the pathogenesis of PD. Based on this progress in the genetics of PD, this review focuses on putative mechanisms of sporadic PD from several angles including oxidative stress, mitochondrial dysfunction and defective proteolysis.

Etiological considerations Most PD cases are sporadic and idiopathic, but only 10–15% of cases are familial owing to Mendelian inheritance. Currently mutations in five genes (termed a-synuclein, parkin, PINK1, DJ-1 and LRRK2; GenBank accession nos. L08850, NM_013988, AB053323, D61380 and AK026776, respectively) definitively cause familial PD. In addition, several chromosomal loci are also linked to familial PD (Table 1) (reviewed in Ref. [2]). Mutations and overexpression of asynuclein cause intracellular inclusions and early rapid onset PD. Lewy bodies, eosinophilic cytoplasmic proteinaceous inclusions composed of fibrillar filaments, are the pathologic hallmarks of the dominantly inherited PD as well as the idiopathic PD. a-Synuclein is a major component of these fibrillar filaments [3]. The discovery that Parkin is involved in UPS, a major route for protein disposal, provided some of the first piece of evidence that proteosome dysfunction plays a www.drugdiscoverytoday.com

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Figure 1. The potential pathways leading to dopaminergic cell death. In brief, reactive oxygen species, which are generated through the oxidative metabolism of DA or via the compromised oxidative phosphorylation in mitochondria by environmental toxins or genetic predispositions, cause modifications in protein homeostasis giving rise to abnormal intracellular protein aggregates, fibrillar deposits of a-synuclein in PD. The ubiquitin– proteosome system (UPS), a major cellular defense mechanism balancing against potential toxicity of protein aggregates, targets the aggregates for proteolytic degradation via the proteosome. Mutations in the parkin gene drift the balance toward the aggregate-prone state, otherwise parkin, an E3 ligase, ubiquitinates substrates for degradation via the UPS. Through the formation of its intermediate multimeric species, such as oligomers and protofibrils, conformational changes of a-synuclein caused by missense mutations or overexpression of wild-type not only show cellular toxicity by themselves but also bring about diverse consequences including defective proteolysis, oxidative stress and mitochondrial defects. In addition, several lines of recent evidence indicate that DJ-1 and PINK1 participate in antioxidative mechanisms and anti-apoptotic pathways, respectively, in a mitochondrial-dependent manner. Derangements occurring in any conceivable steps of these potential pathways seem to converge in detrimental outcomes leading to dopaminergic cell death. Abbreviations: DOPAC: 3,4-dihydroxyphenylacetic acid; DAQ: dopamine quinone; UCH-L1: ubiquitin C-terminal hydrolase; LRRK2: leucine-rich repeat kinase 2; SOD: superoxide dismutase.

role in PD. Recently, two additional recessive genes were isolated, DJ-1 and PINK1. It was reported that the protective role of DJ-1 from oxidative stress was diminished by the loss of function mutations. Although the mechanism by which DJ-1 protects cells is not yet clear, one reasonable explanation is that DJ-1 has an antioxidant role, eliminating hydrogen peroxide through its self-oxidizing capacity [4]. PINK1 has serine/threonine protein kinase activity and resides in mitochondria [5], where there are likely to be important physio428

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logical substrate(s). Currently, there are no reports regarding PINK1 substrates; nevertheless, it is of significance that PINK1 is the first direct link between mitochondria and PD. Most recently, the latest breakthrough in the genetics came from the PD families with the mutations in LRRK2 gene. A single mutation in the gene, G2019S, has been identified as the most commonly known genetic cause in PD, accounting for 1% of sporadic forms and 5% of hereditary PD. Furthermore, the fact that the loss of DA neurons and formation of pro-

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Table 1. Genes associated with PD Gene

Inheritance

Phenotype

Proposed function

a-Synuclein

ADa

Early onset

Binding to SVb

Parkin

ARc

Early onset, no LBd

E3 ligase

UCH-L1

Unclear

Classical PD

Ubiquitin hydrolase

PINK1

AR

Early onset

Mitochondrial kinase

DJ-1

AR

Early onset

Molecular chaperone

LRRK2

AD

Classical PD

Kinase (?)

a

AD: autosomal dominant. SV: synaptic vesicle. c AR: autosomal recessive. d LB: Lewy body. b

teinaceous inclusions in SN are common feature in patients with mutations in LRRK2 suggests an important role of the dardarin protein, the gene product of LRRK2, in the development of PD [6]. Despite the rareness of these genes in causing PD, elucidating the physiological and pathophysiological role of the protein products of the genes in hereditary PD will lead to a better understanding of the sporadic PD. It is also of great importance that the putative molecular pathway and network revealed by genetic studies might also be implicated in the pathogenesis of sporadic PD. As mentioned above, genetic mutations only explain less than 10% of total PD cases, which strongly suggests that nongenetic components are primarily involved in sporadic PD. Although several epidemiological studies show that several factors such as herbicides, pesticides, rural residence and ingestion of well water might increase the risk of PD, the role of the environmental conditions in PD is still not conclusive. Many potentially toxic substances, including trace metals, carbon monoxide, carbon disulfide, cyanide and organic solvents as well as endogenous toxins such as tetrahydroisoquinolines and b-carbolines are thought to be associated with PD, primarily through their mediation of increased oxidative stress [7]. The role of environmental toxins in PD was further defined by recent studies describing novel models of PD based on systemic exposure of animals to toxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), whose toxic properties were encountered by some heroin addicts in the early 1980s, paraquat (PQ), a herbicide, and rotenone, a pesticide. Maneb, which is used in overlapping geographical areas with PQ, has been shown to decrease locomotor activities and potentiate MPTP effects. Together, PD arises from the multiple etiologies including the genetic alterations and environmental factors.

Putative mechanisms Oxidative stress Analysis of post-mortem PD brain indicates that oxidative damage occurs in nigral DA neurons including lipid peroxidation, carbonyl modification of protein and DNA damage.

In addition, decreased levels of reduced glutathione (GSH), glutathione peroxidase and catalase and increased levels of the oxidized glutathione (GSSG) in the mitochondria and abnormalities in iron homeostasis are indicative of increased production of free radicals [8]. Oxidative stress is a detrimental condition that results from increased production or decreased elimination of extremely reactive free radicals including reactive oxygen species (ROS) and reactive nitrogen species (RNS). Normally, ROS might be formed in a variety of cellular processes including mitochondrial oxidative respiration and DA metabolism and effectively detoxified by antioxidant systems, which become less competent by normal aging and disease conditions. Increased oxidative stress can lead to reduced complex I activity and in turn, the activity of complex I is further inhibited owing to a feed forward cycle of oxidative injury because impairment of complex I leads to increased ROS formation. The fact that the dopaminergic system is particularly vulnerable to some environmental toxins and aberrant conditions more than other brain areas suggests that there might exist intrinsic factors in the dopaminergic system, which render the DA neurons susceptible. Some endogenous factors that have been considered significant as potential toxins are DA itself and iron. DA is toxic to a variety of cells both in vivo [9] and in vitro [10]. H2O2 is normally generated in the course of enzymatic deamination of DA by monoamine oxidase (MAO) A and B, which can be converted to the highly reactive hydroxyl radical by the Fenton reaction in the presence of iron or to the superoxide anion. The hydroxyl radical is a highly reactive species capable of modifying intracellular macromolecules irreversibly. Furthermore, DA spontaneously undergoes auto-oxidation to form DA quinone (DAQ) that is capable of covalently modifying sulfhydryl groups and damaging cellular macromolecules [11]. The decrease in the antioxidant defense mechanism and/or the increase in DA metabolism synergistically cause an imbalance in the redox equilibrium, shifting it towards the oxidative stress-prone state and in turn, leads to the relatively selective oxidative damage in DA neurons. Considerable interest has been focused on identifying the factors that facilitate or induce the auto-oxidation of DA and concomitant generation of quinone products. Iron is the most abundant metal in the human body, particularly high in the brain and liver. The potential pathophysiological role of iron in the development of PD are the findings that the levels of iron in the SN of PD brain are not only higher than those in age-matched control and patients with other neurodegenerative disorders but are increased by approximately 35% in PD [12]. Despite the crucial physiological roles of metals in the reaction of many enzymes, their ability to catalyze redox reactions and bind amino acids in proteins can bring about deleterious outcomes. Metal-induced cellular damage can take place throughout the lifetime of an organism, www.drugdiscoverytoday.com

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despite the presence of antioxidant machinery. This is especially true in the brain, in which there are a large number of nondividing cells and a relatively large amount of oxidative products that can accumulate in the cells. This accumulation is particularly evident in the substantia nigra.

Mitochondrial dysfunction The idea of mitochondrial involvement in sporadic PD comes from long lines of studies showing the specificity of mitochondrial complex I deficiency in PD and its localization in the SN [13]. The fact that the complex I defect is similar to that in animal models of PD made by specific neurotoxins, MPTP and rotenone, suggests a causal role for mitochondrial dysfunction in PD. MPTP produces loss of DA neurons in patterns very similar to the pathology of PD in spite of the major limitation of the acute nature of toxicity. MPTP is converted to 1-methyl-4-phenyl pyridium (MPP+) by MAOB and is actively taken up by the DA transporter and then concentrated in DA neurons. In mitochondria, MPP+ selectively binds to and inhibits complex I, causing an uncoupling of ATP synthesis, excessive generation of free radicals and intracellular a-synuclein aggregations [14]. Rotenone, a naturally occurring lipophilic compound, easily crosses the blood–brain barrier. Rotenone causes selective degeneration of nigrostriatal dopaminergic neurons through oxidative damage of striatal dopaminergic terminals and formation of aggregates containing ubiquitin and a-synuclein. Despite the controversy regarding the selectivity of its toxicity, the rotenone model shows that the features of PD can be produced by systemic inhibition of the complex I, implying that the nigrostriatal pathway is intrinsically and selectively sensitive to complex I dysfunction. Exposure to PQ has emerged as a putative risk factor for PD on the basis of its structural similarity to MPP+. When injected systemically into mice, PQ caused parkinsonism in a dose-dependent manner [15] and led to upregulation of and aggregation of a-synuclein [16]. Moreover, family members with maternal inheritance of PD show decreased complex I activity, increased ROS generation, increased antioxidant enzyme activities and abnormal mitochondrial morphological features [17]. More recently, individuals having a certain type of single-nucleotide polymorphism in mitochondrial DNA encoding NADH complex I showed a significant reduced risk of PD [18]. A cytochrome b gene deletion in a PD patient with increased ROS production and a novel mitochondrial 12S rRNA point mutation in a pedigree with parkinsonism and parkinsonism associated with the Leber’s optic atrophy mitochondrial mutation G11778A are consistent with the notion that alterations in complex I activity play causative roles in PD [19]. Taken together, mitochondrial dysfunction through complex I inhibition either through environmental or genetic modifications appears to be one of the major contributors to pathogenesis of PD. 430

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Defective proteolysis The mammalian UPS is an essential cellular machinery that maintains protein homeostasis through protein quality control and the degradation of target proteins. Substrates are polyubiquitinated through the serial actions of E1 (ubiquitinactivating), E2 (ubiquitin-conjugating) and E3 (ubiquitinligating) enzymes. Once they have been polyubiquinated, substrates are recognized by the 26S proteosome, which consists of one 20S proteolytic and two 19S regulatory subunits for the degradation [20]. The fact that protein aggregation and inclusion body formation are common pathological phenomena in many neurodegenerative diseases implies central role of protein misfolding in development of these diseases, although whether the inclusion body is protective or toxic to neurons is still undetermined. The possibility of UPS involvement in the pathogenesis of PD is suggested through the post-mortem analysis of PD brains, which showed a relatively selective loss of 20S activity [21]. Moreover, direct links between a defective UPS and PD came from genetic cases of PD harboring mutations in parkin. Autopsies on patients with parkin mutations usually show lack of Lewy bodies, suggesting that parkin might play a role in the formation of the inclusions.

Parkin Parkin, the causative gene of autosomal recessive juvenile parkinsonism (ARJP), is an E3 ligase adding ubiquitin to target proteins, which targets them for proteolytic degradation in the proteosome [22]. Loss of function mutations of parkin is thought to cause the accumulation of one or more parkin substrates. Recently, we reported that the parkin substrate, p38/JTV-1 (AIMP2, interacting factor of aminoacyl-tRNA synthetase complex), was found to be increased in parkin null mice, in brains of ARJP patients and even in sporadic PD brain. In addition, it is selectively toxic to DA neurons in vitro and in vivo. p38/JTV-1 appears to be an authentic pathogenic substrate of parkin [23]. Moreover, parkin might function in novel intracellular signaling because parkin ubiquitinates proteins not only via lysine 48(K48) for proteosomal degradation, but also via lysine 63(K63) for signaling processes and Lewy body formation [24].

a-Synuclein a-Synuclein is a major structural component of the pathological intracellular inclusions of aggregates designated, Lewy bodies. A direct role for a-synuclein in PD was provided by genetic studies. Autosomal dominant PD occurs through three distinct missense mutations (A53T, A30P and E46K) in a-synuclein or via overexpression of wild-type a-synuclein through genomic duplication or triplication. a-Synuclein is a natively unfolded monomeric protein both located in the cytosol and is associated with presynaptic vesicles, which implies a role for a-synuclein in regulating synaptic vesicle

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homeostasis and neurotransmission [25]. a-Synuclein appears to exist in heterogeneous conformations including soluble monomers, soluble oligomers (protofibrils) and insoluble filaments depending on intrinsic and extrinsic factors such as the missense mutations, concentration, post-translational modifications and oxidative stress (reviewed in Ref. [25]). In addition, b-synuclein and g-synuclein might act as antiaggregation factors for a-synuclein and inhibit a-synuclein toxicity in vivo [26]. There are several lines of evidence indicating that aggregated a-synuclein oligomers, in turn, cause oxidative stress and mitochondrial dysfunction, leading to the subsequent death of DA neurons (reviewed in Ref. [27]). Moreover, formation of nigral inclusions containing ubiquitin and a-synuclein in patterns very similar to the pathology of PD was reported following chronic continuous infusion of MPTP [28], which implicate an intimate relationship between mitochondrial dysfunction and altered a-synuclein homeostasis. Recently, a novel finding on the toxic mechanism of mutations in a-synuclein gene that the mutations inhibit translocation of a-synuclein and other substrates into the lysosome for chaperone-mediated autophagy was reported [29]. Synergistic interactions also seems to be there between a-synuclein and tau, driving the formation of pathological inclusions [30].

DJ-1 DJ-1 is another gene causing autosomal recessive parkinsonism. Although the normal function and its role in dopaminergic degeneration still remain elusive, recent lines of evidence in Drosophila suggest that DJ-1 is involved in antioxidative defense mechanisms and its mutants showed selective sensitivity to environmental toxins including rotenone and paraquat [31]. In addition, loss of function mutations of DJ-1 in mice showed functional impairment of the nigrostriatal dopaminergic circuit and hypoactivity in the open field, which indicates a putative physiological role of DJ-1 in neurotransmission [32]. DJ-1 was originally cloned as a novel oncogene transforming NIH-3T3 cells together with Hras [33]. Its involvement in this signaling pathway as a negative regulator of tumor suppressor PTEN, which modulates the phosphatidylinositol 3 kinase (PI3K) pathway, might underlie its normal physiologic function [34].

PINK1 Recently, mutations in PINK1 (PTEN-induced kinase 1) gene have been reported to cause autosomal recessive early-onset parkinsonism. PINK1 encodes a putative serine–threonine protein kinase and is transcriptionally transactivated by PTEN. Its mitochondrial localization and protective roles against cell death also imply that PINK1 might be involved in the mitochondrial-dependent cell death pathway [35]. Moreover, PD-related mutations in PINK1 were reported to abolish its protective functions against neuronal apoptotic

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processes such as cytochrome c release, caspase activation and poly(ADP-ribose) polymerase (PARP) activation [36]. Despite its rareness as a genetic cause of PD, it is particularly interesting in terms of linking mitochondrial dysfunction to PD.

LRRK2 The discovery of mutations in the LRRK2 gene is promising for the future understanding of PD. First, one mutation, G2019S, is the most common cause of autosomal dominant PD in up to 5–6% of familial PD cases and in even 1–2% of patients with sporadic PD. Second, phenotypic presentations including L-DOPA responsiveness, dementia and degeneration of SN, are very similar to those seen in sporadic PD, which suggests that LRRK2 is even more relevant to development of PD than all other PD genes identified thus far. Despite the clinical features of patients with LRRK2 mutations, there are different sets of pathology in each case. A variety of heterogeneous inclusions such as Lewy body, tau positive aggregates or ubiquitin-positive filamentous lesions have been reported. Based on our recent results, LRRK2 is localized mainly in cytoplasm tethered to the mitochondria and disease-related mutations had no apparent effects on protein homeostasis and localization. According to in vitro kinase assays, mutants showed an increase in activity in both autophosphorylation and phosphorylation of a generic substrate, indicating a gainof-function mechanism in the development of PD due to LRRK2 mutations [37]. Moreover, these results suggest that inhibitors of LRRK2 might be of therapeutic benefit in the treatment of PD.

Conclusion There have been tremendous advances in our knowledge on the pathogenesis of PD in the past few years, accompanying the progress in the genetics of PD. In summary, PD is a multifactorial disease attributed to several factors working in conjunction, such as intracellular toxic aggregates formed either through oxidative modification, mitochondrial dysfunction due to environmental toxicants, genetic alterations and the preferential susceptibility of DA neuron itself to these aberrant conditions. The role of misfolded a-synuclein and alterations in the UPS are emerging from obscurity as common pathogenic pathways contributing to the pathology of PD. However, there are still important issues to be resolved. First, what renders DA neurons more vulnerable to the asynuclein oligomers, in spite of the fact that a-synuclein is normally expressed in all kinds of cells throughout the brain? The fact that DA neurons reside in oxidation-prone milieu and show particular sensitivity to environmental toxins might lead in part to the increased susceptibility. PD fundamentally seems to be a sporadic disease. Can the mechanisms elucidated from the studies on hereditary PD contribute to universal pathway that is relevant for sporadic PD? Underwww.drugdiscoverytoday.com

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Table 2. Medical therapies for PD: present and future Targets

Agents

Symptomatic Increase DAa content

Reduce DA metabolism

Refs Based on [39]

DA precursor (L-DOPA) DA receptor agonist Monoamine reuptake inhibitor Adenosine A2A receptor antagonist 5-HT1A receptor agonist MAO-Bb inhibitor COMTc inhibitor

Anticholinergic Neuroprotective Oxidative stress

Mitochondrial dysfunction Excitotoxicity Inflammation

Apoptosis

Cell death UPSk

Neurorestorative Trophic factors Cell transplantation Gene therapy

Vitamins C and E Metal chelator ROS scavenger MAO-B inhibitor Coenzyme Q10 Energy mimetics NMDAd antagonist AMPAe receptor antagonist iNOSf inhibitor PPARgg inhibitor Minocycline Caspase inhibitor p53 inhibitor GAPDHh translocation inhibitor nNOSi inhibitors PARPj inhibitors E3 ligase mimics Proteosomal enhancer Inhibitor of a-Synl toxicity Inhibitor of phosphorylation of a-Syn

Based on [38,40] [7,8,11]

[13]

[13]

[20]

Based on [38] GDNFm, Nurturin GPI-1485 (neuroimmunophilin ligand) Stem cells, precursor cells GDNF, Nurturin

a

DA: dopamine. MAO: monoamine oxidase. COMT: catechol-o-methyltransferase. d NMDA: N-methyl-D-aspartate. e AMPA: a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. f iNOS: inducible NO synthase. g PPAR: peroxisome proliferator activated receptor. h GAPDH: glyceraldehyde 3-phosphate dehydrogenase. i nNOS: neuronal nitric oxide(NO) synthase. j PARP: poly(ADP-ribose) polymerase. k UPS: ubiquitin–proteosome system. l a-Syn: a-synuclein. m GDNF: glial-derived nerve growth factor. b c

standing the interrelationship between mitochondrial dysfunction, oxidative stress and aberrant protein homeostasis might help elucidate the link and lead us to new arenas of therapeutic intervention (Table 2) (reviewed in Ref. [38]).

Acknowledgements Supported by grants from the NIH, NINDS NS 38377, NS 051468, NS 047565, the Lee Martin Trust, the Sylvia Nachlas Trust, the National Parkinson Foundation and the American Parkinson’s Disease Association. S.W.K. is the Herbert Freid432

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berg Fellow in Parkinson’s Disease Research. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases.

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