Journal of Parkinson’s Disease 3 (2013) 461–491 461 DOI 10.3233/JPD-130230 IOS Press Review The Role of Oxidative Stress in Parkinson’s Disease Vera Dias, Eunsung Junn and M. Maral Mouradian∗ Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, NJ, USA Abstract. Oxidative stress plays an important role in the degeneration of dopaminergic neurons in Parkinson’s disease (PD). Disruptions in the physiologic maintenance of the redox potential in neurons interfere with several biological processes, ultimately leading to cell death. Evidence has been developed for oxidative and nitrative damage to key cellular components in the PD substantia nigra. A number of sources and mechanisms for the generation of reactive oxygen species (ROS) are recognized including the metabolism of dopamine itself, mitochondrial dysfunction, iron, neuroinflammatory cells, calcium, and aging. PD causing gene products including DJ-1, PINK1, parkin, alpha-synuclein and LRRK2 also impact in complex ways mitochondrial function leading to exacerbation of ROS generation and susceptibility to oxidative stress. Additionally, cellular homeostatic processes including the ubiquitin-proteasome system and mitophagy are impacted by oxidative stress. It is apparent that the interplay between these various mechanisms contributes to neurodegeneration in PD as a feed forward scenario where primary insults lead to oxidative stress, which damages key cellular pathogenetic proteins that in turn cause more ROS production. Animal models of PD have yielded some insights into the molecular pathways of neuronal degeneration and highlighted previously unknown mechanisms by which oxidative stress contributes to PD. However, therapeutic attempts to target the general state of oxidative stress in clinical trials have failed to demonstrate an impact on disease progression. Recent knowledge gained about the specific mechanisms related to PD gene products that modulate ROS production and the response of neurons to stress may provide targeted new approaches towards neuroprotection. Keywords: Neurodegeneration, neuroprotection, neuroinflammation, reactive oxygen species, dopamine, mitochondria INTRODUCTION neurons [3–7]. This is supported by postmortem brain analyses showing increased levels of 4-hydroxyl-2- The mechanisms responsible for neuronal degen- nonenal (HNE), a by-product of lipid peroxidation [8, eration in Parkinson’s disease (PD) are complex and 9], carbonyl modifications of soluble proteins [10], remain to be fully elucidated. Among the various and DNA and RNA oxidation products 8-hydroxy- neuronal types that degenerate in this disease, there deoxyguanosine and 8-hydroxy-guanosine [11, 12]. is little doubt that the loss of dopaminergic neu- The link between oxidative stress and dopaminergic rons in the substantia nigra pars compacta (SNpc) neuronal degeneration is further supported by model- is responsible for the characteristic motor symptoms ing the motor aspects of PD in animals with toxins that and drives symptomatic therapies [1, 2]. Accumu- cause oxidative stress including 1-methyl-4-phenyl- lating evidence indicates that oxidative damage and 1,2,3,6-tetrahydropyridine (MPTP), rotenone, 1,1’- mitochondrial dysfunction contribute to the cascade of dimethyl-4,4’-bipyridinium dichloride (paraquat), and events leading to degeneration of these dopaminergic 6-hydroxydopamine (6-OHDA) [13–17]. In addition ∗ to PD, several other neurodegenerative disorders Correspondence to: M. Maral Mouradian, Rutgers - RWJMS, including Alzheimer’s disease, Huntington’s disease, 683 Hoes Lane West, Room 180, Piscataway, NJ 08854, USA. Tel.: +1 732 235 4772; Fax: +1 732 235 4773; E-mail: m.mouradian@ and amyotrophic lateral sclerosis are associated with rutgers.edu. oxidative stress as well, despite having distinct ISSN 1877-7171/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License. 462 V. Dias et al. / The Role of Oxidative Stress in Parkinson’s Disease pathological and clinical features [18] suggesting that in glial cells [27–29]. NO is present within cells oxidative stress is a common mechanism contributing and in the extracellular space surrounding dopamin- to neuronal degeneration [19, 20]. ergic neurons produced by either nNOS or iNOS [30]. Here we review the role of oxidative stress in the Additionally, with gliosis, activated glial cells that pathogenesis of PD, its effects on cellular homeosta- express iNOS may contribute to increased NO levels sis, the biochemical and molecular events that mediate [31, 32]. NO inhibits several enzymes including com- or regulate neuronal vulnerability, and the role of plexes I and IV of the mitochondrial electron transport PD-related gene products in modulating the cellular chain, leading to ROS generation. It also reacts with responses to oxidative stress in the course of neurode- proteins to form S-nitrosothiols thus altering their func- generation. tion, and with lipids causing their lipid peroxidation [25]. Peroxynitrite, which is oxidatively a more active THE BIOCHEMISTRY OF OXIDATIVE molecule and a more potent oxidizing agent than NO, STRESS can induce DNA fragmentation and lipid peroxidation [25, 26]. Peroxynitrite also induces a dose-dependent Oxidative stress defines a disequilibrium between impairment in dopamine synthesis independent of the levels of reactive oxygen species (ROS) produced dopamine oxidation or cell death [26]. Exposure of and the ability of a biological system to detoxify the tyrosine hydroxylase (TH), the rate-limiting enzyme reactive intermediates, creating a perilous state con- in dopamine synthesis, to peroxynitrite results in nitra- tributing to cellular damage. tion of tyrosine residues and modification of cysteines ROS can be generated through several pathways leading to decreased catalytic activity [33, 34]. The such as direct interactions between redox-active metals role of NO in PD is supported by postmortem brain and oxygen species via reactions including the Fen- tissue analyses showing increased expression of iNOS ton and Haber-Weiss reactions, or by indirect pathways and nNOS in basal ganglia structures using in situ involving the activation of enzymes such as nitric oxide hybridization and immunohistochemical studies [35, synthase (NOS) or NADPH oxidases. As a general 36]. Experimentally in the MPTP model, the gliosis in principle, the chemical origin of the majority of free the SN is associated with significant up-regulation of radicals requires the activation of molecular oxygen iNOS [37], while inhibition of nNOS protects against [21]. Examples of ROS include the superoxide anion MPTP toxicity [38, 39]. Together, these observations 2− • radical (O2 ), hydroxyl radical ( OH) and hydrogen suggest that NO and its metabolite peroxynitrite may peroxide (H2O2). Superoxide anion, which is produced play a role in PD. mainly by mitochondrial complexes I and III of the All organisms have developed adaptive responses to electron transport chain, is highly reactive and can eas- oxidative stress that result in increased production of ily cross the inner mitochondrial membrane, where it defensive enzymes, molecular chaperones and antiox- can be reduced to H2O2. Besides being produced by idant molecules [40]. Under physiologic conditions, mitochondria, H2O2 can also be generated by peroxi- ROS are involved in signaling events mediated by somes [22]. As peroxisomes contain catalase, H2O2 is thiol residues in proteins that have the potential to converted to water, preventing its accumulation. How- regulate transcription [41]. On the other hand, under ever,whenperoxisomesaredamagedandtheirenzymes conditions of oxidative stress, free radical-mediated down-regulated, H2O2 is released to the cytosol where oxidative damage occurs at various sites within the it contributes to oxidative stress. In the presence of cell such as peroxidation of cellular membrane lipids 2+ reducedmetalssuchasferrousiron(Fe ),H2O2 canbe resulting in the generation of toxic products includ- convertedbytheFentonreactionintothehighlyreactive ing HNE and malondialdehyde [9], protein oxidation hydroxyl radical, the most harmful of all ROS [23]. demonstrated by cross-linking and fragmentation as Besides ROS, evidence also exists for the involve- well as carbonyl group formation [10, 42], and DNA ment of reactive nitrogen species (RNS) in mediating and RNA oxidation [11]. nitrosative stress [24]. RNS are generated by the quick reaction of superoxide with nitric oxide (NO), which ROS PRODUCTION IN THE PD BRAIN results in the production of large amounts of per- oxynitrite (ONOO.−) [25, 26]. NO is produced by The extensive production of ROS in the brain may NO synthase (NOS) [27], which has three isoforms, provide an explanation for the magnitude of the role endothelial NOS (eNOS), neuronal NOS (nNOS) iden- that these reactive molecules play in PD. The brain tified in neurons, and inducible NOS (iNOS) identified consumes about 20% of the oxygen supply of the body, V. Dias et al. / The Role of Oxidative Stress in Parkinson’s Disease 463 and a significant portion of that oxygen is converted to the generation of superoxide and depletion of cellular ROS [43]. ROS can be generated in the brain from sev- NADPH. Aminochrome can form adducts with pro- eral sources, both in neurons and glia, with the electron teins such as alpha-synuclein