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Mitochondrial dysfunction in Parkinson’s disease: a possible target for neuroprotection

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  • Published:
Frontiers in Biology

Abstract

Mitochondria are dynamic organelles which are required for maintaining cellular homeostasis. Thus, it is not surprising that irregularities in mitochondrial function result in cellular damage and are linked with neurodegenerative diseases, such as Parkinson’s disease. Evidence that mitochondrial dysfunction is key to the pathogenesis of Parkinson’s disease is founded in studies in post-mortem tissue from patients with Parkinson’s disease, and also from genetic studies stemming from patients with familial Parkinson’s disease. Whether triggered by environmental or genetic factors, mitochondrial dysfunction occurs early in the pathogenic process, and is central to Parkinson’s disease pathology. As such, targeting the mitochondria to slow or halt disease progression is an attractive strategy for disease-modifying agents in Parkinson’s disease. Indeed, several therapies which target the mitochondria have been investigated as neuroprotective treatments for Parkinson’s disease. This review will discuss the evidence supporting mitochondrial dysfunction in Parkinson’s disease pathology as well as treatment strategies that target the mitochondria.

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References

  • Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, Colombo L, Manzoni C, Salmona M, Caccia S, Negro A, Forloni G (2009). The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by alpha-synuclein or amyloid-beta (1-42) peptide. J Neurochem, 110(5): 1445–1456

    CAS  PubMed  Google Scholar 

  • Andres R H, Huber A W, Schlattner U, Pérez-Bouza A, Krebs S H, Seiler R W, Wallimann T, Widmer H R (2005). Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue. Neuroscience, 133(3): 701–713

    CAS  PubMed  Google Scholar 

  • Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco T M, Thomas B, Ko H S, Sasaki M, Ischiropoulos H, Przedborski S, Dawson T M, Dawson V L (2007). DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci USA, 104(37): 14807–14812

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bedford L, Hay D, Devoy A, Paine S, Powe D G, Seth R, Gray T, Topham I, Fone K, Rezvani N, Mee M, Soane T, Layfield R, Sheppard P W, Ebendal T, Usoskin D, Lowe J, Mayer R J (2008). Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci, 28: 8189–8198

    CAS  PubMed  Google Scholar 

  • Beher D, Wu J, Cumine S, Kim K W, Lu S C, Atangan L, Wang M (2009). Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des, 74(6): 619–624

    CAS  PubMed  Google Scholar 

  • Bender A, Krishnan K J, Morris C M, Taylor G A, Reeve A K, Perry R H, Jaros E, Hersheson J S, Betts J, Klopstock T, Taylor R W, Turnbull DM (2006). High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet, 38(5): 515–517

    CAS  PubMed  Google Scholar 

  • Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973). Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci, 20(4): 415–455

    CAS  Google Scholar 

  • Blackinton J, Lakshminarasimhan M, Thomas K J, Ahmad R, Greggio E, Raza A S, Cookson M R, Wilson M A (2009). Formation of a stabilized cysteine sulfinic acid is critical for the mitochondrial function of the parkinsonism protein DJ-1. J Biol Chem, 284(10): 6476–6485

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bové J, Zhou C, Jackson-Lewis V, Taylor J, Chu Y, Rideout H J, Wu D C, Kordower J H, Petrucelli L, Przedborski S (2006). Proteasome inhibition and Parkinson’s disease modeling. Ann Neurol, 60(2): 260–264

    PubMed  Google Scholar 

  • Brunet A, Sweeney L B, Sturgill J F, Chua K F, Greer P L, Lin Y, Tran H, Ross S E, Mostoslavsky R, Cohen H Y, Hu L S, Cheng H L, Jedrychowski M P, Gygi S P, Sinclair D A, Alt F W, Greenberg M E (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science, 303(5666): 2011–2015

    CAS  PubMed  Google Scholar 

  • Canet-Avilés R M, Wilson M A, Miller D W, Ahmad R, McLendon C, Bandyopadhyay S, Baptista M J, Ringe D, Petsko G A, Cookson MR (2004). The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci USA, 101(24): 9103–9108

    PubMed Central  PubMed  Google Scholar 

  • Chan C S, Gertler T S, Surmeier D J (2010). A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson’s disease. Mov Disord, 25(Suppl 1): S63–70

    PubMed  Google Scholar 

  • Chan C S, Guzman J N, Ilijic E, Mercer J N, Rick C, Tkatch T, Meredith G E, Surmeier D J (2007). ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature, 447(7148): 1081–1086

    CAS  PubMed  Google Scholar 

  • Chao J, Yu M S, Ho Y S, Wang M, Chang R C (2008). Dietary oxyresveratrol prevents parkinsonian mimetic 6-hydroxydopamine neurotoxicity. Free Radic Biol Med, 45(7): 1019–1026

    CAS  PubMed  Google Scholar 

  • Chartier-Harlin M C, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, Levecque C, Larvor L, Andrieux J, Hulihan M, Waucquier N, Defebvre L, Amouyel P, Farrer M, Destée A (2004). Alphasynuclein locus duplication as a cause of familial Parkinson’s disease. Lancet, 364(9440): 1167–1169

    CAS  PubMed  Google Scholar 

  • Cherra S J 3rd, Steer E, Gusdon A M, Kiselyov K, Chu C T (2013). Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am J Pathol, 182(2): 474–484

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chinta S J, Mallajosyula J K, Rane A, Andersen J K (2010). Mitochondrial α-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci Lett, 486(3): 235–239

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ciron C, Lengacher S, Dusonchet J, Aebischer P, Schneider B L (2012). Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function. Hum Mol Genet, 21(8): 1861–1876

    CAS  PubMed Central  PubMed  Google Scholar 

  • Clark I E, Dodson M W, Jiang C, Cao J H, Huh J R, Seol J H, Yoo S J, Hay B A, Guo M (2006). Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature, 441(7097): 1162–1166

    CAS  PubMed  Google Scholar 

  • Cole N B, Murphy D D (2002). The cell biology of alpha-synuclein: a sticky problem? Neuromolecular Med, 1(2): 95–109

    CAS  PubMed  Google Scholar 

  • Cookson M R (2003). Parkin’s substrates and the pathways leading to neuronal damage. Neuromolecular Med, 3(1): 1–13

    CAS  PubMed  Google Scholar 

  • Couzin J (2007). Clinical research. Testing a novel strategy against Parkinson’s disease. Science, 315(5820): 1778

    CAS  PubMed  Google Scholar 

  • Cuervo A M, Stefanis L, Fredenburg R, Lansbury P T, Sulzer D (2004). Impaired degradation of mutant alpha-synuclein by chaperonemediated autophagy. Science, 305(5688): 1292–1295

    CAS  PubMed  Google Scholar 

  • Dauer W, Przedborski S (2003). Parkinson’s disease: mechanisms and models. Neuron, 39(6): 889–909

    CAS  PubMed  Google Scholar 

  • Devi L, Raghavendran V, Prabhu B M, Avadhani N G, Anandatheerthavarada H K (2008). Mitochondrial import and accumulation of alphasynuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem, 283(14): 9089–9100

    CAS  PubMed Central  PubMed  Google Scholar 

  • Donmez G, Arun A, Chung C Y, McLean P J, Lindquist S, Guarente L (2012). SIRT1 protects against alpha-synuclein aggregation by activating molecular chaperones. J Neurosci, 32: 124–132

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dorsey E R, Constantinescu R, Thompson J P, Biglan K M, Holloway R G, Kieburtz K, Marshall F J, Ravina B M, Schifitto G, Siderowf A, Tanner C M (2007). Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology, 68(5): 384–386

    CAS  PubMed  Google Scholar 

  • Dryanovski D I, Guzman J N, Xie Z, Galteri D J, Volpicelli-Daley L A, Lee V M, Miller R J, Schumacker P T, Surmeier D J (2013). Calcium entry and alpha-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons. J Neurosci, 33(24): 10154–10164

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ekstrand M I, Terzioglu M, Galter D, Zhu S, Hofstetter C, Lindqvist E, Thams S, Bergstrand A, Hansson F S, Trifunovic A, Hoffer B, Cullheim S, Mohammed A H, Olson L, Larsson N G (2007). Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci USA, 104(4): 1325–1330

    CAS  PubMed Central  PubMed  Google Scholar 

  • Esteves A R, Lu J, Rodova M, Onyango I, Lezi E, Dubinsky R, Lyons K E, Pahwa R, Burns J M, Cardoso S M, Swerdlow R H (2010). Mitochondrial respiration and respiration-associated proteins in cell lines created through Parkinson’s subject mitochondrial transfer. J Neurochem, 113(3): 674–682

    CAS  PubMed  Google Scholar 

  • Exner N, Lutz A K, Haass C, Winklhofer K F (2012). Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J, 31(14): 3038–3062

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ferretta A, Gaballo A, Tanzarella P, Piccoli C, Capitanio N, Nico B, Annese T, Di Paola M, Dell’aquila C, De Mari M, Ferranini E, Bonifati V, Pacelli C, Cocco T (2014). Effect of resveratrol on mitochondrial function: implications in parkin-associated familiar Parkinson’s disease. Biochim Biophys Acta, 1842(7): 902–915

    CAS  PubMed  Google Scholar 

  • Frye R A (2000). Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun, 273(2): 793–798

    CAS  PubMed  Google Scholar 

  • Fuchs J, Nilsson C, Kachergus J, Munz M, Larsson E M, Schüle B, Langston J W, Middleton F A, Ross O A, Hulihan M, Gasser T, Farrer M J (2007). Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology, 68(12): 916–922

    CAS  PubMed  Google Scholar 

  • Gautier C A, Kitada T, Shen J (2008). Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci USA, 105(32): 11364–11369

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gerhart-Hines Z, Rodgers J T, Bare O, Lerin C, Kim S H, Mostoslavsky R, Alt F W, Wu Z, Puigserver P (2007). Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J, 26(7): 1913–1923

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gispert S, Ricciardi F, Kurz A, Azizov M, Hoepken H H, Becker D, Voos W, Leuner K, Müller W E, Kudin A P, Kunz W S, Zimmermann A, Roeper J, Wenzel D, Jendrach M, García-Arencíbia M, Fernández-Ruiz J, Huber L, Rohrer H, Barrera M, Reichert A S, Rüb U, Chen A, Nussbaum R L, Auburger G (2009). Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS ONE, 4(6): e5777

    PubMed Central  PubMed  Google Scholar 

  • Goedert M (2001). Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci, 2(7): 492–501

    CAS  PubMed  Google Scholar 

  • Goldberg M S, Fleming S M, Palacino J J, Cepeda C, Lam H A, Bhatnagar A, Meloni E G, Wu N, Ackerson L C, Klapstein G J, Gajendiran M, Roth B L, Chesselet M F, Maidment N T, Levine M S, Shen J (2003). Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem, 278(44): 43628–43635

    CAS  PubMed  Google Scholar 

  • Gómez-Sánchez R, Gegg M E, Bravo-San Pedro J M, Niso-Santano M, Alvarez-Erviti L, Pizarro-Estrella E, Gutiérrez-Martín Y, Alvarez-Barrientos A, Fuentes JM, González-Polo R A, Schapira A H (2014). Mitochondrial impairment increases FL-PINK1 levels by calciumdependent gene expression. Neurobiol Dis, 62: 426–440

    PubMed Central  PubMed  Google Scholar 

  • González-Polo R, Niso-Santano M, Morán JM, Ortiz-Ortiz MA, Bravo-San Pedro J M, Soler G, Fuentes J M (2009). Silencing DJ-1 reveals its contribution in paraquat-induced autophagy. J Neurochem, 109(3): 889–898

    PubMed  Google Scholar 

  • Good C H, Hoffman A F, Hoffer B J, Chefer V I, Shippenberg T S, Backman CM, Larsson N G, Olson L, Gellhaar S, Galter D, Lupica C R (2011). Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson’s disease. FASEB J, 25:1333–1344

    CAS  PubMed Central  PubMed  Google Scholar 

  • Greenamyre J T, Betarbet R, Sherer T B (2003). The rotenone model of Parkinson’s disease: genes, environment and mitochondria. Parkinsonism Relat Disord, 9(Suppl 2): S59–S64

    PubMed  Google Scholar 

  • Greene J C, Whitworth A J, Kuo I, Andrews L A, Feany M B, Pallanck L J (2003). Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci USA, 100(7): 4078–4083

    CAS  PubMed Central  PubMed  Google Scholar 

  • Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, Kaganovich A, van der Brug M P, Beilina A, Blackinton J, Thomas K J, Ahmad R, Miller D W, Kesavapany S, Singleton A, Lees A, Harvey R J, Harvey K, Cookson M R (2006). Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis, 23(2): 329–341

    CAS  PubMed  Google Scholar 

  • Gu G, Reyes P E, Golden G T, Woltjer R L, Hulette C, Montine T J, Zhang J (2002). Mitochondrial DNA deletions/rearrangements in parkinson disease and related neurodegenerative disorders. J Neuropathol Exp Neurol, 61(7): 634–639

    CAS  PubMed  Google Scholar 

  • Guardia-Laguarta C, Area-Gomez E, Rub C, Liu Y, Magrane J, Becker D, Voos W, Schon E A, Przedborski S (2014). alpha-Synuclein is localized to mitochondria-associated ER membranes. J Neurosc, 34: 249–259

    CAS  Google Scholar 

  • Guzman J N, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker P T, Surmeier D J (2010). Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature, 468(7324): 696–700

    CAS  PubMed  Google Scholar 

  • Haas R H, Nasirian F, Nakano K, Ward D, Pay M, Hill R, Shults C W (1995). Low platelet mitochondrial complex I and complex II/III activity in early untreated Parkinson’s disease. Ann Neurol, 37(6): 714–722

    CAS  PubMed  Google Scholar 

  • Hayashi Y, Yoshida M, Yamato M, Ide T, Wu Z, Ochi-Shindou M, Kanki T, Kang D, Sunagawa K, Tsutsui H, Nakanishi H (2008). Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice. J Neurosci, 28: 8624–8634

    CAS  PubMed  Google Scholar 

  • Healy D G, Abou-Sleiman P M, Casas J P, Ahmadi K R, Lynch T, Gandhi S, Muqit M M, Foltynie T, Barker R, Bhatia K P, Quinn N P, Lees A J, Gibson J M, Holton J L, Revesz T, Goldstein D B, Wood N W (2006). UCHL-1 is not a Parkinson’s disease susceptibility gene. Ann Neurol, 59(4): 627–633

    CAS  PubMed  Google Scholar 

  • Höglinger G U, Carrard G, Michel P P, Medja F, Lombès A, Ruberg M, Friguet B, Hirsch E C (2003). Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson’s disease. J Neurochem, 86(5): 1297–1307

    PubMed  Google Scholar 

  • Howitz K T, Bitterman K J, Cohen H Y, Lamming DW, Lavu S, Wood J G, Zipkin R E, Chung P, Kisielewski A, Zhang L L, Scherer B, Sinclair D A (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 425(6954): 191–196

    CAS  PubMed  Google Scholar 

  • Ikebe S, Tanaka M, Ozawa T (1995). Point mutations of mitochondrial genome in Parkinson’s disease. Brain Res Mol Brain Res, 28(2): 281–295

    CAS  PubMed  Google Scholar 

  • Imai Y, Soda M, Takahashi R (2000). Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem, 275(46): 35661–35664

    CAS  PubMed  Google Scholar 

  • Inden M, Taira T, Kitamura Y, Yanagida T, Tsuchiya D, Takata K, Yanagisawa D, Nishimura K, Taniguchi T, Kiso Y, Yoshimoto K, Agatsuma T, Koide-Yoshida S, Iguchi-Ariga S M, Shimohama S, Ariga H (2006). PARK7 DJ-1 protects against degeneration of nigral dopaminergic neurons in Parkinson’s disease rat model. Neurobiol Dis, 24(1): 144–158

    CAS  PubMed  Google Scholar 

  • Irrcher I, Aleyasin H, Seifert E L, Hewitt S J, Chhabra S, Phillips M, Lutz A K, Rousseaux M W, Bevilacqua L, Jahani-Asl A, Callaghan S, MacLaurin J G, Winklhofer K F, Rizzu P, Rippstein P, Kim R H, Chen C X, Fon E A, Slack R S, Harper M E, McBride H M, Mak T W, Park D S (2010). Loss of the Parkinson’s disease-linked gene DJ-1 perturbs mitochondrial dynamics. Hum Mol Genet, 19(19): 3734–3746

    CAS  PubMed  Google Scholar 

  • Itier JM, Ibanez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme G A, Laville M, Pratt J, Corti O, Pradier L, Ret G, Joubert C, Periquet M, Araujo F, Negroni J, Casarejos M J, Canals S, Solano R, Serrano A, Gallego E, Sanchez M, Denefle P, Benavides J, Tremp G, Rooney T A, Brice A, Garcia de Yebenes J (2003). Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet, 12(18): 2277–2291

    CAS  PubMed  Google Scholar 

  • Jin F, Wu Q, Lu Y F, Gong Q H, Shi J S (2008). Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson’s disease in rats. Eur J Pharmacol, 600(1-3): 78–82

    CAS  PubMed  Google Scholar 

  • Juhn M S, Tarnopolsky M (1998). Oral creatine supplementation and athletic performance: a critical review. Clin J Sport Med, 8: 286–297

    CAS  PubMed  Google Scholar 

  • Kakefuda K, Fujita Y, Oyagi A, Hyakkoku K, Kojima T, Umemura K, Tsuruma K, Shimazawa M, Ito M, Nozawa Y, Hara H (2009). Sirtuin 1 overexpression mice show a reference memory deficit, but not neuroprotection. Biochem Biophys Res Commun, 387(4): 784–788

    CAS  PubMed  Google Scholar 

  • Katzenschlager R, Lees A J (2002). Treatment of Parkinson’s disease: levodopa as the first choice. J Neurol, 249(Suppl 2): II19–II24

    PubMed  Google Scholar 

  • Keeney P M, Quigley C K, Dunham L D, Papageorge C M, Iyer S, Thomas R R, Schwarz K M, Trimmer P A, Khan S M, Portell F R, Bergquist K E, Bennett J P Jr (2009). Mitochondrial gene therapy augments mitochondrial physiology in a Parkinson’s disease cell model. Hum Gene Ther, 20(8): 897–907

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kim R H, Smith P D, Aleyasin H, Hayley S, Mount M P, Pownall S, Wakeham A, You-Ten A J, Kalia S K, Horne P, Westaway D, Lozano A M, Anisman H, Park D S, Mak T W (2005). Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci USA, 102(14): 5215–5220

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 392(6676): 605–608

    CAS  PubMed  Google Scholar 

  • Kitada T, Pisani A, Porter D R, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C, Pothos E N, Shen J (2007). Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci USA, 104(27): 11441–11446

    CAS  PubMed Central  PubMed  Google Scholar 

  • Klivenyi P, Gardian G, Calingasan N Y, Yang L, Beal M F (2003). Additive neuroprotective effects of creatine and a cyclooxygenase 2 inhibitor against dopamine depletion in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. J Mol Neurosci, MN 21: 191–198

    CAS  Google Scholar 

  • Klivenyi P, Calingasan N Y, Starkov A, Stavrovskaya I G, Kristal B S, Yang L, Wieringa B, Beal M F (2004). Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase. Neurobiol Dis, 15(3): 610–617

    CAS  PubMed  Google Scholar 

  • Klivenyi P, Siwek D, Gardian G, Yang L, Starkov A, Cleren C, Ferrante R J, Kowall N W, Abeliovich A, Beal M F (2006). Mice lacking alpha-synuclein are resistant to mitochondrial toxins. Neurobiol Dis, 21(3): 541–548

    CAS  PubMed  Google Scholar 

  • Kones R (2010). Mitochondrial therapy for Parkinson’s disease: neuroprotective pharmaconutrition may be disease-modifying. Clin pharmacol, 2: 185–198

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kordower J H, Kanaan N M, Chu Y, Suresh Babu R, Stansell J 3rd, Terpstra B T, Sortwell C E, Steece-Collier K, Collier T J (2006). Failure of proteasome inhibitor administration to provide a model of Parkinson’s disease in rats and monkeys. Ann Neurol, 60(2): 264–268

    CAS  PubMed  Google Scholar 

  • Kraytsberg Y, Kudryavtseva E, McKee A C, Geula C, Kowall N W, Khrapko K (2006). Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet, 38(5): 518–520

    CAS  PubMed  Google Scholar 

  • Krebiehl G, Ruckerbauer S, Burbulla L F, Kieper N, Maurer B, Waak J, Wolburg H, Gizatullina Z, Gellerich F N, Woitalla D, Riess O, Kahle P J, Proikas-Cezanne T, Krüger R (2010). Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson’s disease-associated protein DJ-1. PLoS ONE, 5(2): e9367

    PubMed Central  PubMed  Google Scholar 

  • Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen J T, Schöls L, Riess O (1998). Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet, 18(2): 106–108

    PubMed  Google Scholar 

  • Lakshminarasimhan M, Rauh D, Schutkowski M, Steegborn C (2013). Sirt1 activation by resveratrol is substrate sequence-selective. Aging (Albany NY), 5(3): 151–154

    CAS  Google Scholar 

  • Langston J W, Ballard P, Tetrud J W, Irwin I (1983). Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science, 219(4587): 979–980

    CAS  PubMed  Google Scholar 

  • Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein M J, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach P J, Wilkinson K D, Polymeropoulos M H (1998). The ubiquitin pathway in Parkinson’s disease. Nature, 395(6701): 451–452

    CAS  PubMed  Google Scholar 

  • Li C, Beal M F (2005). Leucine-rich repeat kinase 2: a new player with a familiar theme for Parkinson’s disease pathogenesis. Proc Natl Acad Sci USA, 102(46): 16535–16536

    CAS  PubMed Central  PubMed  Google Scholar 

  • Li X, Kazgan N (2011). Mammalian sirtuins and energy metabolism. Int J Biol Sci, 7(5): 575–587

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lim K L (2007). Ubiquitin-proteasome system dysfunction in Parkinson’s disease: current evidence and controversies. Expert Rev Proteomics, 4(6): 769–781

    CAS  PubMed  Google Scholar 

  • Lin T K, Chen S D, Chuang Y C, Lin H Y, Huang C R, Chuang J H, Wang P W, Huang S T, Tiao M M, Chen J B, Liou C W (2014). Resveratrol partially prevents rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through induction of heme oxygenase-1 dependent autophagy. Int J Mol Sci, 15(1): 1625–1646

    PubMed Central  PubMed  Google Scholar 

  • Liu D, Gharavi R, Pitta M, Gleichmann M, Mattson M P (2009). Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons. Neuromolecular Med, 11(1): 28–42

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liu G, Zhang C, Yin J, Li X, Cheng F, Li Y, Yang H, Uéda K, Chan P, Yu S (2009). alpha-Synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity. Neurosci Lett, 454(3): 187–192

    CAS  PubMed  Google Scholar 

  • Lu K T, Ko M C, Chen B Y, Huang J C, Hsieh C W, Lee M C, Chiou R Y, Wung B S, Peng C H, Yang Y L (2008). Neuroprotective effects of resveratrol on MPTP-induced neuron loss mediated by free radical scavenging. J Agric Food Chem, 56(16): 6910–6913

    CAS  PubMed  Google Scholar 

  • Lutz A K, Exner N, Fett M E, Schlehe J S, Kloos K, Lämmermann K, Brunner B, Kurz-Drexler A, Vogel F, Reichert A S, Bouman L, Vogt-Weisenhorn D, Wurst W, Tatzelt J, Haass C, Winklhofer K F (2009). Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem, 284(34): 22938–22951

    CAS  PubMed Central  PubMed  Google Scholar 

  • Marques O, Outeiro T F (2012). Alpha-synuclein: from secretion to dysfunction and death. Cell Death Dis, 3(7): e350

    CAS  PubMed Central  PubMed  Google Scholar 

  • Matthews R T, Ferrante R J, Klivenyi P, Yang L, Klein A M, Mueller G, Kaddurah-Daouk R, Beal M F (1999). Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol, 157(1): 142–149

    CAS  PubMed  Google Scholar 

  • McLelland G L, Soubannier V, Chen C X, McBride H M, Fon E A (2014). Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J, 33(4): 282–295

    CAS  PubMed  Google Scholar 

  • McNaught K S, Perl D P, Brownell A L, Olanow C W (2004). Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann Neurol, 56(1): 149–162

    CAS  PubMed  Google Scholar 

  • Minakawa E N, Yamakado H, Tanaka A, Uemura K, Takeda S, Takahashi R (2013). Chicken DT40 cell line lacking DJ-1, the gene responsible for familial Parkinson’s disease, displays mitochondrial dysfunction. Neurosci Res, 77(4): 228–233

    CAS  PubMed  Google Scholar 

  • Moisoi N, Fedele V, Edwards J, Martins L M (2014). Loss of PINK1 enhances neurodegeneration in a mouse model of Parkinson’s disease triggered by mitochondrial stress. Neuropharmacology, 77: 350–357

    CAS  PubMed Central  PubMed  Google Scholar 

  • Morais V A, Haddad D, Craessaerts K, De Bock P J, Swerts J, Vilain S, Aerts L, Overbergh L, Grünewald A, Seibler P, Klein C, Gevaert K, Verstreken P, De Strooper B (2014). PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling. Science, 344(6180): 203–207

    CAS  PubMed  Google Scholar 

  • Mortiboys H, Johansen K K, Aasly J O, Bandmann O (2010). Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2. Neurology, 75(22): 2017–2020

    CAS  PubMed  Google Scholar 

  • Mortiboys H, Thomas K J, Koopman W J, Klaffke S, Abou-Sleiman P, Olpin S, Wood N W, Willems P H, Smeitink J A, Cookson M R, Bandmann O (2008). Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol, 64(5): 555–565

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mudò G, Mäkelä J, Di Liberto V, Tselykh T V, Olivieri M, Piepponen P, Eriksson O, Mälkiä A, Bonomo A, Kairisalo M, Aguirre J A, Korhonen L, Belluardo N, Lindholm D (2012). Transgenic expression and activation of PGC-1α protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease. Cell Mol Life Sci, 69(7): 1153–1165

    PubMed  Google Scholar 

  • Murray A M, Weihmueller F B, Marshall J F, Hurtig H I, Gottleib G L, Joyce J N (1995). Damage to dopamine systems differs between Parkinson’s disease and Alzheimer’s disease with parkinsonism. Ann Neurol, 37(3): 300–312

    CAS  PubMed  Google Scholar 

  • Narendra D, Tanaka A, Suen D F, Youle R J (2008). Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol, 183(5): 795–803

    CAS  PubMed Central  PubMed  Google Scholar 

  • Neuspiel M, Schauss A C, Braschi E, Zunino R, Rippstein P, Rachubinski R A, Andrade-Navarro M A, McBride H M (2008). Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers. Curr Biol, CB 18: 102–108

    CAS  Google Scholar 

  • Ng C H, Mok S Z, Koh C, Ouyang X, Fivaz M L, Tan E K, Dawson V L, Dawson T M, Yu F, Lim K L (2009). Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila. J Neurosci, 29: 11257–11262

    CAS  PubMed Central  PubMed  Google Scholar 

  • NINDS NET-PD Investigators (2006). A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology, 66(5): 664–671

    Google Scholar 

  • Nishiyama S, Shitara H, Nakada K, Ono T, Sato A, Suzuki H, Ogawa T, Masaki H, Hayashi J, Yonekawa H (2010). Over-expression of Tfam improves the mitochondrial disease phenotypes in a mouse model system. Biochem Biophys Res Commun, 401(1): 26–31

    CAS  PubMed  Google Scholar 

  • Niu J, Yu M, Wang C, Xu Z (2012). Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via Dynamin-like protein. J Neurochem, 122(3): 650–658

    CAS  PubMed  Google Scholar 

  • Noack H, Bednarek T, Heidler J, Ladig R, Holtz J, Szibor M (2006). TFAM-dependent and independent dynamics of mtDNA levels in C2C12 myoblasts caused by redox stress. Biochim Biophys Acta, 1760(2): 141–150

    CAS  PubMed  Google Scholar 

  • O’Donnell K C, Lulla A, Stahl M C, Wheat N D, Bronstein J M, Sagasti A (2014). Axon degeneration and PGC-1α-mediated protection in a zebrafish model of α-synuclein toxicity. Dis Model Mech, 7(5): 571–582

    PubMed Central  PubMed  Google Scholar 

  • Orenstein S J, Kuo S H, Tasset I, Arias E, Koga H, Fernandez-Carasa I, Cortes E, Honig L S, Dauer W, Consiglio A, Raya A, Sulzer D, Cuervo A M (2013). Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci, 16(4): 394–406

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pacholec M, Bleasdale J E, Chrunyk B, Cunningham D, Flynn D, Garofalo R S, Griffith D, Griffor M, Loulakis P, Pabst B, Qiu X, Stockman B, Thanabal V, Varghese A, Ward J, Withka J, Ahn K (2010). SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem, 285(11): 8340–8351

    CAS  PubMed Central  PubMed  Google Scholar 

  • Papkovskaia T D, Chau K Y, Inesta-Vaquera F, Papkovsky D B, Healy D G, Nishio K, Staddon J, Duchen M R, Hardy J, Schapira A H, Cooper J M (2012). G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization. Hum Mol Genet, 21(19): 4201–4213

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pardo P S, Mohamed J S, Lopez M A, Boriek A M (2011). Induction of Sirt1 by mechanical stretch of skeletal muscle through the early response factor EGR1 triggers an antioxidative response. J Biol Chem, 286(4): 2559–2566

    CAS  PubMed Central  PubMed  Google Scholar 

  • Parihar M S, Parihar A, Fujita M, Hashimoto M, Ghafourifar P (2008). Mitochondrial association of alpha-synuclein causes oxidative stress. Cell Mol Life Sci, 65(7-8): 1272–1284

    CAS  PubMed  Google Scholar 

  • Park J, Kim S Y, Cha G H, Lee S B, Kim S, Chung J (2005). Drosophila DJ-1 mutants show oxidative stress-sensitive locomotive dysfunction. Gene, 361: 133–139

    CAS  PubMed  Google Scholar 

  • Park J, Lee S B, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim J M, Chung J (2006). Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature, 441(7097): 1157–1161

    CAS  PubMed  Google Scholar 

  • Parker W D Jr, Boyson S J, Parks J K (1989). Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol, 26(6): 719–723

    PubMed  Google Scholar 

  • Pesah Y, Pham T, Burgess H, Middlebrooks B, Verstreken P, Zhou Y, Harding M, Bellen H, Mardon G (2004). Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development, 131(9): 2183–2194

    CAS  PubMed  Google Scholar 

  • Ping H X, Shepard P D (1999). Blockade of SK-type Ca2+-activated K+ channels uncovers a Ca2+-dependent slow afterdepolarization in nigral dopamine neurons. J Neurophysiol, 81(3): 977–984

    CAS  PubMed  Google Scholar 

  • Polymeropoulos M H, Lavedan C, Leroy E, Ide S E, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos E S, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson W G, Lazzarini A M, Duvoisin R C, Di Iorio G, Golbe L I, Nussbaum R L (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 276(5321): 2045–2047

    CAS  PubMed  Google Scholar 

  • Poole A C, Thomas R E, Andrews L A, McBride H M, Whitworth A J, Pallanck L J (2008). The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA, 105(5): 1638–1643

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ramirez A, Heimbach A, Gründemann J, Stiller B, Hampshire D, Cid L P, Goebel I, Mubaidin A F, Wriekat A L, Roeper J, Al-Din A, Hillmer A M, Karsak M, Liss B, Woods C G, Behrens M I, Kubisch C (2006). Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet, 38(10): 1184–1191

    CAS  PubMed  Google Scholar 

  • Ramonet D, Daher J P, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing D A, Beal M F, Troncoso J C, McCaffery JM, Jenkins N A, Copeland N G, Galter D, Thomas B, Lee M K, Dawson T M, Dawson V L, Moore D J (2011). Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS ONE, 6(4): e18568

    CAS  PubMed Central  PubMed  Google Scholar 

  • Richfield E K, Thiruchelvam M J, Cory-Slechta D A, Wuertzer C, Gainetdinov R R, Caron M G, Di Monte D A, Federoff H J (2002). Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol, 175(1): 35–48

    CAS  PubMed  Google Scholar 

  • Saha S, Guillily M D, Ferree A, Lanceta J, Chan D, Ghosh J, Hsu C H, Segal L, Raghavan K, Matsumoto K, Hisamoto N, Kuwahara T, Iwatsubo T, Moore L, Goldstein L, Cookson M, Wolozin B (2009). LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J Neurosci, 29: 9210–9218

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sakata E, Yamaguchi Y, Kurimoto E, Kikuchi J, Yokoyama S, Yamada S, Kawahara H, Yokosawa H, Hattori N, Mizuno Y, Tanaka K, Kato K (2003). Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain. EMBO Rep, 4(3): 301–306

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sarafian T A, Ryan C M, Souda P, Masliah E, Kar U K, Vinters H V, Mathern G W, Faull K F, Whitelegge J P, Watson J B (2013). Impairment of mitochondria in adult mouse brain overexpressing predominantly full-length, N-terminally acetylated human α-synuclein. PLoS ONE, 8(5): e63557 PMID:23667637

    CAS  PubMed Central  PubMed  Google Scholar 

  • Scarffe L A, Stevens D A, Dawson V L, Dawson T M (2014). Parkin and PINK1: much more than mitophagy. Trends Neurosci, 37(6): 315–324

    CAS  PubMed  Google Scholar 

  • Schapira A H, Cooper J M, Dexter D, Jenner P, Clark J B, Marsden C D (1989). Mitochondrial complex I deficiency in Parkinson’s disease. Lancet, 1(8649): 1269

    CAS  PubMed  Google Scholar 

  • Shavali S, Brown-Borg H M, Ebadi M, Porter J (2008). Mitochondrial localization of alpha-synuclein protein in alpha-synuclein overexpressing cells. Neurosci Lett, 439(2): 125–128

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (2000). Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet, 25(3): 302–305

    CAS  PubMed  Google Scholar 

  • Shin J H, Ko H S, Kang H, Lee Y, Lee Y I, Pletinkova O, Troconso J C, Dawson V L, Dawson T M (2011). PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease. Cell, 144(5): 689–702

    CAS  PubMed Central  PubMed  Google Scholar 

  • Simon D K, Lin M T, Zheng L, Liu G J, Ahn C H, Kim L M, Mauck W M, Twu F, Beal M F, Johns D R (2004). Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson’s disease. Neurobiol Aging, 25(1): 71–81

    CAS  PubMed  Google Scholar 

  • Snyder H, Mensah K, Theisler C, Lee J, Matouschek A, Wolozin B (2003). Aggregated and monomeric alpha-synuclein bind to the S6′ proteasomal protein and inhibit proteasomal function. J Biol Chem, 278(14): 11753–11759

    CAS  PubMed  Google Scholar 

  • Song D D, Shults C W, Sisk A, Rockenstein E, Masliah E (2004). Enhanced substantia nigra mitochondrial pathology in human alphasynuclein transgenic mice after treatment with MPTP. Exp Neurol, 186(2): 158–172

    CAS  PubMed  Google Scholar 

  • Soubannier V, McLelland G L, Zunino R, Braschi E, Rippstein P, Fon E A, McBride H M (2012). A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr Biol, CB 22: 135–141

    CAS  Google Scholar 

  • Spillantini M G, Crowther R A, Jakes R, Hasegawa M, Goedert M (1998). alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci USA, 95(11): 6469–6473

    CAS  PubMed Central  PubMed  Google Scholar 

  • Spillantini M G, Schmidt M L, Lee V M, Trojanowski J Q, Jakes R, Goedert M (1997). Alpha-synuclein in Lewy bodies. Nature, 388(6645): 839–840

    CAS  PubMed  Google Scholar 

  • St-Pierre J, Drori S, Uldry M, Silvaggi J M, Rhee J, Jäger S, Handschin C, Zheng K, Lin J, Yang W, Simon D K, Bachoo R, Spiegelman B M (2006). Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 127(2): 397–408

    CAS  PubMed  Google Scholar 

  • Su Y C, Qi X (2013). Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet, 22(22): 4545–4561

    CAS  PubMed  Google Scholar 

  • Sulzer D, Zecca L (2000). Intraneuronal dopamine-quinone synthesis: a review. Neurotox Res, 1(3): 181–195

    CAS  PubMed  Google Scholar 

  • Surmeier D J (2007). Calcium, ageing, and neuronal vulnerability in Parkinson’s disease. Lancet Neurol, 6(10): 933–938

    CAS  PubMed  Google Scholar 

  • Surmeier D J, Guzman J N, Sanchez-Padilla J (2010). Calcium, cellular aging, and selective neuronal vulnerability in Parkinson’s disease. Cell Calcium, 47(2): 175–182

    CAS  PubMed Central  PubMed  Google Scholar 

  • Taira T, Saito Y, Niki T, Iguchi-Ariga S M, Takahashi K, Ariga H (2004). DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep, 5(2): 213–218

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tanaka M, Kim Y M, Lee G, Junn E, Iwatsubo T, Mouradian M M (2004). Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem, 279(6): 4625–4631

    CAS  PubMed  Google Scholar 

  • Valente E M, Abou-Sleiman P M, Caputo V, Muqit M M, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio A R, Healy D G, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks W P, Latchman D S, Harvey R J, Dallapiccola B, Auburger G, Wood N W (2004). Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science, 304(5674): 1158–1160

    CAS  PubMed  Google Scholar 

  • Valente E M, Salvi S, Ialongo T, Marongiu R, Elia A E, Caputo V, Romito L, Albanese A, Dallapiccola B, Bentivoglio A R (2004). PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol, 56(3): 336–341

    CAS  PubMed  Google Scholar 

  • van der Horst A, Tertoolen L G, de Vries-Smits L M, Frye R A, Medema R H, Burgering B M (2004). FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2 (SIRT1). J Biol Chem, 279(28): 28873–28879

    PubMed  Google Scholar 

  • Vaquero A, Scher M, Erdjument-Bromage H, Tempst P, Serrano L, Reinberg D (2007). SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature, 450(7168): 440–444

    CAS  PubMed  Google Scholar 

  • Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D (2004). Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell, 16(1): 93–105

    CAS  PubMed  Google Scholar 

  • Wang X, Winter D, Ashrafi G, Schlehe J, Wong Y L, Selkoe D, Rice S, Steen J, LaVoie M J, Schwarz T L (2011). PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell, 147(4): 893–906

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang X, Yan M H, Fujioka H, Liu J, Wilson-Delfosse A, Chen S G, Perry G, Casadesus G, Zhu X (2012). LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum Mol Genet, 21(9): 1931–1944

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wareski P, Vaarmann A, Choubey V, Safiulina D, Liiv J, Kuum M, Kaasik A (2009). PGC-1alpha and PGC-1beta regulate mitochondrial density in neurons. J Biol Chem, 284(32): 21379–21385

    CAS  PubMed Central  PubMed  Google Scholar 

  • West A B, Moore D J, Biskup S, Bugayenko A, Smith W W, Ross C A, Dawson V L, Dawson T M (2005). Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA, 102(46): 16842–16847

    CAS  PubMed Central  PubMed  Google Scholar 

  • Westerheide S D, Anckar J, Stevens S M Jr, Sistonen L, Morimoto R I (2009). Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science, 323(5917): 1063–1066

    CAS  PubMed Central  PubMed  Google Scholar 

  • Winslow A R, Chen C W, Corrochano S, Acevedo-Arozena A, Gordon D E, Peden A A, Lichtenberg M, Menzies F M, Ravikumar B, Imarisio S, Brown S, O’Kane C J, Rubinsztein D C (2010). α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol, 190(6): 1023–1037

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wood-Kaczmar A, Gandhi S, Yao Z, Abramov A Y, Miljan E A, Keen G, Stanyer L, Hargreaves I, Klupsch K, Deas E, Downward J, Mansfield L, Jat P, Taylor J, Heales S, Duchen M R, Latchman D, Tabrizi S J, Wood N W (2008). PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE, 3(6): e2455

    PubMed Central  PubMed  Google Scholar 

  • Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L (2009). Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS ONE, 4(5): e5515

    PubMed Central  PubMed  Google Scholar 

  • Yang S R, Wright J, Bauter M, Seweryniak K, Kode A, Rahman I (2007). Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-kappaB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging. Am J Physiol Lung Cel l Mol Physiol, 292(2): L567–L576

    CAS  Google Scholar 

  • Yeung F, Hoberg J E, Ramsey C S, Keller M D, Jones D R, Frye R A, Mayo M W (2004). Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J, 23(12): 2369–2380

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yong-Kee C J, Salomonczyk D, Nash J E (2011). Development and validation of a screening assay for the evaluation of putative neuroprotective agents in the treatment of Parkinson’s disease. Neurotox Res, 19(4): 519–526

    CAS  PubMed  Google Scholar 

  • Yong-Kee C J, Sidorova E, Hanif A, Perera G, Nash J E (2012). Mitochondrial dysfunction precedes other sub-cellular abnormalities in an in vitro model linked with cell death in Parkinson’s disease. Neurotox Res, 21(2): 185–194

    CAS  PubMed  Google Scholar 

  • Zarranz J J, Alegre J, Gómez-Esteban J C, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atarés B, Llorens V, Gomez Tortosa E, del Ser T, Muñoz D G, de Yebenes J G (2004). The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol, 55(2): 164–173

    CAS  PubMed  Google Scholar 

  • Zhang L, Shimoji M, Thomas B, Moore D J, Yu S W, Marupudi N I, Torp R, Torgner I A, Ottersen O P, Dawson T M, Dawson V L (2005). Mitochondrial localization of the Parkinson’s disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet, 14(14): 2063–2073

    CAS  PubMed  Google Scholar 

  • Zhang N Y, Tang Z, Liu CW (2008). alpha-Synuclein protofibrils inhibit 26 S proteasome-mediated protein degradation: understanding the cytotoxicity of protein protofibrils in neurodegenerative disease pathogenesis. J Biol Chem, 283(29): 20288–20298

    CAS  PubMed  Google Scholar 

  • Zheng B, Liao Z, Locascio J J, Lesniak K A, Roderick S S, Watt M L, Eklund A C, Zhang-James Y, Kim P D, Hauser M A, Grünblatt E, Moran L B, Mandel S A, Riederer P, Miller R M, Federoff H J, Wüllner U, Papapetropoulos S, Youdim M B, Cantuti-Castelvetri I, Young A B, Vance J M, Davis R L, Hedreen J C, Adler C H, Beach T G, Graeber M B, Middleton F A, Rochet J C, Scherzer C R, Global P D G E C, and the Global PD Gene Expression (GPEX) Consortium (2010). PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med, 2(52): 52ra73

    PubMed Central  PubMed  Google Scholar 

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  1. Centre for Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, M1C1A4, Canada

    Jacqueline A. Gleave, Peter D. Perri & Joanne E. Nash

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Gleave, J.A., Perri, P.D. & Nash, J.E. Mitochondrial dysfunction in Parkinson’s disease: a possible target for neuroprotection. Front. Biol. 9, 489–503 (2014). https://doi.org/10.1007/s11515-014-1337-8

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