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Dopamine and Paraquat Enhance α-Synuclein-Induced Alterations in Membrane Conductance

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Abstract

We have previously demonstrated that α-synuclein overexpression increases the membrane conductance of dopaminergic-like cells. Although α-synuclein is thought to play a central role in the pathogenesis of several neurodegenerative diseases including Parkinson’s disease, multiple system atrophy, and diffuse Lewy body disease, the mechanism of action is not completely understood. In this study, we sought to determine whether multiple factors act together with α-synuclein to engender cell vulnerability through an augmentation of membrane conductance. In this article, we employed a cell model that mimics dopaminergic neurons coupled with α-synuclein overexpression and oxidative stressors. We demonstrate an enhancement of α-synuclein-induced toxicity in the presence of combined treatment with dopamine and paraquat, two molecules known to incite oxidative stress. In addition, we show that combined dopamine and paraquat treatment increases the expression of heme oxygenase-1, an antioxidant response protein. Finally, we demonstrate for the first time that combined treatment of dopaminergic cells with paraquat and dopamine enhances α-synuclein-induced leak channel properties resulting in increased membrane conductance. Importantly, these increases are most robust when both paraquat and dopamine are present suggesting the need for multiple oxidative insults to augment α-synuclein-induced disruption of membrane integrity.

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References

  • Abeliovich A, Schmitz Y, Fariñas I, Choi-Lundberg D, Ho W-H, Castillo PE, Shinsky N, Verdugo JMG, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A (2000) Mice lacking [alpha]-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252

    Article  PubMed  CAS  Google Scholar 

  • Alam ZI, Daniel SE, Lees AJ, Marsden DC, Jenner P, Halliwell B (1997a) A generalised increase in protein carbonyls in the brain in Parkinson’s but not incidental lewy body disease. J Neurochem 69:1326–1329

    Article  PubMed  CAS  Google Scholar 

  • Alam ZI, Jenner A, Daniel SE, Lees AJ, Cairns N, Marsden CD, Jenner P, Halliwell B (1997b) Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem 69:1196–1203

    Article  PubMed  CAS  Google Scholar 

  • Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 90:7915–7922

    Article  PubMed  CAS  Google Scholar 

  • Auluck PK, Caraveo G, Lindquist S (2010) α-Synuclein: membrane interactions and toxicity in Parkinson’s disease. Annu Rev Cell Dev Biol 26:211–233

    Article  PubMed  CAS  Google Scholar 

  • Barbeau A, Dallaire L, Buu N, Poirier J, Rucinska E (1985) Comparative behavioral, biochemical and pigmentary effects of MPTP, MPP+ and paraquat in Rana pipiens. Life Sci 37:1529–1538

    Article  PubMed  CAS  Google Scholar 

  • Beal MF (2003) Mitochondria, oxidative damage, and inflammation in Parkinson’s disease. Ann N Y Acad Sci 991:120–131

    Article  PubMed  CAS  Google Scholar 

  • Bisaglia M, Mammi S, Bubacco L (2007) Kinetic and structural analysis of the early oxidation products of dopamine. J Biol Chem 282:15597–15605

    Article  PubMed  CAS  Google Scholar 

  • Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464:529–535

    Article  PubMed  CAS  Google Scholar 

  • Black AT, Gray JP, Shakarjian MP, Laskin DL, Heck DE, Laskin JD (2008) Increased oxidative stress and antioxidant expression in mouse keratinocytes following exposure to paraquat. Toxicol Appl Pharmacol 231:384–392

    Article  PubMed  CAS  Google Scholar 

  • Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134

    Article  PubMed  Google Scholar 

  • Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff HJ (1999) Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res 823:1–10

    Article  PubMed  CAS  Google Scholar 

  • Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC (2010) {Alpha}-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329:1663–1667

    Article  PubMed  CAS  Google Scholar 

  • Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R, Lu B, Nussbaum RL (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22:8797–8807

    PubMed  CAS  Google Scholar 

  • Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, Kraft AD, Lee J-M, Li J, Johnson JA (2009) The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal 11:497–508

    Article  PubMed  CAS  Google Scholar 

  • Cappai R, Leck S-L, Tew DJ, Williamson NA, Smith DP, Galatis D, Sharples RA, Curtain CC, Ali FE, Cherny RA, Culvenor JG, Bottomley SP, Masters CL, Barnham KJ, Hill AF (2005) Dopamine promotes alpha-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway. FASEB J 19:1377–1379

    PubMed  CAS  Google Scholar 

  • Carvey PM, Punati A, Newman MB (2006) Progressive dopamine neuron loss in Parkinson’s disease: the multiple hit hypothesis. Cell Transplant 15:239–250

    Article  PubMed  Google Scholar 

  • Caudle WM, Colebrooke RE, Emson PC, Miller GW (2008) Altered vesicular dopamine storage in Parkinson’s disease: a premature demise. Trends Neurosci 31:303–308

    Article  PubMed  CAS  Google Scholar 

  • Caughey B, Lansbury PT (2003) Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26:267–298

    Article  PubMed  CAS  Google Scholar 

  • Chen CXQ, Huang SY, Zhang L, Liu Y-J (2005) Synaptophysin enhances the neuroprotection of VMAT2 in MPP+-induced toxicity in MN9D cells. Neurobiol Dis 19:419–426

    Article  PubMed  CAS  Google Scholar 

  • Chen P-C, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, Johnson JA (2009) Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: critical role for the astrocyte. Proc Natl Acad Sci USA 106:2933–2938

    Article  PubMed  CAS  Google Scholar 

  • Choi HK, Won LA, Kontur PJ, Hammond DN, Fox AP, Wainer BH, Hoffmann PC, Heller A (1991) Immortalization of embryonic mesencephalic dopaminergic neurons by somatic cell fusion. Brain Res 552:67–76

    Article  PubMed  CAS  Google Scholar 

  • Choi H, Won L, Roback J, Wainer B, Heller A (1992) Specific modulation of dopamine expression in neuronal hybrid cells by primary cells from different brain regions. Proc Natl Acad Sci USA 89:8943–8947

    Article  PubMed  CAS  Google Scholar 

  • Cicchetti F, Drouin-Ouellet J, Gross RE (2009) Environmental toxins and Parkinson’s disease: what have we learned from pesticide-induced animal models? Trends Pharmacol Sci 30:475–483

    Article  PubMed  CAS  Google Scholar 

  • Clejan L, Cederbaum AI (1989) Synergistic interactions between nadph-cytochrome P-450 reductase, paraquat, and iron in the generation of active oxygen radicals. Biochem Pharmacol 38:1779–1786

    Article  PubMed  CAS  Google Scholar 

  • Cocheme HM, Murphy MP (2008) Complex I is the major site of mitochondrial superoxide production by paraquat. J Biol Chem 283:1786–1798

    Article  PubMed  CAS  Google Scholar 

  • Conway KA, Harper JD, Lansbury PT (1998) Accelerated in vitro fibril formation by a mutant [alpha]-synuclein linked to early-onset Parkinson disease. Nat Med 4:1318–1320

    Article  PubMed  CAS  Google Scholar 

  • Conway KA, Rochet JC, Bieganski RM, Lansbury PT Jr (2001) Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science 294:1346–1349

    Article  PubMed  CAS  Google Scholar 

  • Cookson MR (2005) The biochemistry of Parkinson’s disease. Annu Rev Biochem 74:29–52

    Article  PubMed  CAS  Google Scholar 

  • Cookson MR, van der Brug M (2008) Cell systems and the toxic mechanism(s) of alpha-synuclein. Exp Neurol 209:5–11

    Article  PubMed  CAS  Google Scholar 

  • Cory-Slechta DA, Thiruchelvam M, Barlow BK, Richfield EK (2005) Developmental pesticide models of the Parkinson disease phenotype. Environ Health Perspect 113:1263–1270

    Article  PubMed  CAS  Google Scholar 

  • Croisier E, Moran LB, Dexter DT, Pearce RKB, Graeber MB (2005) Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J Neuroinflammation 2:14

    Article  PubMed  CAS  Google Scholar 

  • Danzer KM, Haasen D, Karow AR, Moussaud S, Habeck M, Giese A, Kretzschmar H, Hengerer B, Kostka M (2007) Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci 27:9220–9232

    Article  PubMed  CAS  Google Scholar 

  • Darios F, Ruiperez V, Lopez I, Villanueva J, Gutierrez LM, Davletov B (2010) [Alpha]-synuclein sequesters arachidonic acid to modulate SNARE-mediated exocytosis. EMBO Rep 11:528–533

    Article  PubMed  CAS  Google Scholar 

  • Davie CA (2008) A review of Parkinson’s disease. Br Med Bull 86:109–127

    Article  PubMed  CAS  Google Scholar 

  • Day BJ, Patel M, Calavetta L, Chang L-Y, Stamler JS (1999) A mechanism of paraquat toxicity involving nitric oxide synthase. Proc Natl Acad Sci USA 96:12760–12765

    Article  PubMed  CAS  Google Scholar 

  • Dexter DT, Carter CJ, Wells FR, Javoy-Agid F, Agid Y, Lees A, Jenner P, Marsden CD (1989) Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem 52:381–389

    Article  PubMed  CAS  Google Scholar 

  • Dexter DT, Holley AE, Flitter WD, Slater TF, Wells FR, Daniel SE, Lees AJ, Jenner P, Marsden CD (1994) Increased levels of lipid hydroperoxides in the parkinsonian substantia nigra: an HPLC and ESR study. Mov Disord 9:92–97

    Article  PubMed  CAS  Google Scholar 

  • Di Monte DA, Lavasani M, Manning-Bog AB (2002) Environmental factors in Parkinson’s disease. Neurotoxicology 23:487–502

    Article  PubMed  CAS  Google Scholar 

  • Dicker E, Cederbaum AI (1991) NADH-dependent generation of reactive oxygen species by microsomes in the presence of iron and redox cycling agents. Biochem Pharmacol 42:529–535

    Article  PubMed  CAS  Google Scholar 

  • Ding TT, Lee S-J, Rochet J-C, Lansbury PT Jr (2002) Annular alpha-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes. Biochemistry 41:10209–10217

    Article  PubMed  CAS  Google Scholar 

  • Dinis-Oliveira RJ, Remião F, Carmo H, Duarte JA, Navarro AS, Bastos ML, Carvalho F (2006) Paraquat exposure as an etiological factor of Parkinson’s disease. Neurotoxicology 27:1110–1122

    Article  PubMed  CAS  Google Scholar 

  • Dong Y, Heien ML, Maxson MM, Ewing AG (2008) Amperometric measurements of catecholamine release from single vesicles in MN9D cells. J Neurochem 107:1589–1595

    Article  PubMed  CAS  Google Scholar 

  • Duda JE, Lee VMY, Trojanowski JQ (2000) Neuropathology of synuclein aggregates. J Neurosci Res 61:121–127

    Article  PubMed  CAS  Google Scholar 

  • Eisenhofer G, Kopin IJ, Goldstein DS (2004) Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev 56:331–349

    Article  PubMed  CAS  Google Scholar 

  • El-Agnaf OMA, Salem SA, Paleologou KE, Cooper LJ, Fullwood NJ, Gibson MJ, Curran MD, Court JA, Mann DMA, Ikeda S-I, Cookson MR, Hardy J, Allsop D (2003) Alpha-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB J 17:1945–1947

    PubMed  CAS  Google Scholar 

  • Elbaz A, Dufouil C, Alpérovitch A (2007) Interaction between genes and environment in neurodegenerative diseases. C R Biol 330:318–328

    Article  PubMed  CAS  Google Scholar 

  • Engel L, Checkoway H, Keifer M, Seixas N, Longstreth W, Scott K, Hudnell K, Anger W, Camicioli R (2001) Parkinsonism and occupational exposure to pesticides. Occup Environ Med 58:582–589

    Article  PubMed  CAS  Google Scholar 

  • Fei Q, McCormack AL, Di Monte DA, Ethell DW (2008) Paraquat neurotoxicity is mediated by a Bak-dependent mechanism. J Biol Chem 283:3357–3364

    Article  PubMed  CAS  Google Scholar 

  • Feng LR, Federoff HJ, Vicini S, Maguire-Zeiss KA (2010) α-Synuclein mediates alterations in membrane conductance: a potential role for α-synuclein oligomers in cell vulnerability. Eur J Neurosci 32:10–17

    Article  Google Scholar 

  • Fernagut PO, Hutson CB, Fleming SM, Tetreaut NA, Salcedo J, Masliah E, Chesselet MF (2007) Behavioral and histopathological consequences of paraquat intoxication in mice: effects of alpha-synuclein over-expression. Synapse 61:991–1001

    Article  PubMed  CAS  Google Scholar 

  • Fink AL (2006) The aggregation and fibrillation of α-synuclein. Acc Chem Res 39:628–634

    Article  PubMed  CAS  Google Scholar 

  • Fortin DL, Nemani VM, Voglmaier SM, Anthony MD, Ryan TA, Edwards RH (2005) Neural activity controls the synaptic accumulation of {alpha}-synuclein. J Neurosci 25:10913–10921

    Article  PubMed  CAS  Google Scholar 

  • Furukawa K, Matsuzaki-Kobayashi M, Hasegawa T, Kikuchi A, Sugeno N, Itoyama Y, Wang Y, Yao PJ, Bushlin I, Takeda A (2006) Plasma membrane ion permeability induced by mutant alpha-synuclein contributes to the degeneration of neural cells. J Neurochem 97:1071–1077

    Article  PubMed  CAS  Google Scholar 

  • Goldberg MS, Lansbury PT Jr (2000) Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson’s disease? Nat Cell Biol 2:E115–E119

    Article  PubMed  CAS  Google Scholar 

  • Gorell J, Johnson C, Rybicki B, Peterson E, Richardson R (1998) The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 50:1346–1350

    PubMed  CAS  Google Scholar 

  • Graham DG, Tiffany SM, Bell WR, Gutknecht WF (1978) Autoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward C1300 neuroblastoma cells in vitro. Mol Pharmacol 14:644–653

    PubMed  CAS  Google Scholar 

  • Greenamyre JT, Hastings TG (2004) Biomedicine: Parkinson’s—divergent causes, convergent mechanisms. Science 304:1120–1122

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA, Payami H (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 42:781–785

    Article  PubMed  CAS  Google Scholar 

  • Hawkes CH, Tredici KD, Braak H (2009) Parkinson’s disease. Ann N Y Acad Sci 1170:615–622

    Article  PubMed  Google Scholar 

  • Heller KB, Poser B, Haest CWM, Deuticke B (1984) Oxidative stress of human erythrocytes by iodate and periodate Reversible formation of aqueous membrane pores due to SH-group oxidation. Biochim Biophys Acta Biomembranes 777:107–116

    Article  CAS  Google Scholar 

  • Herishanu YO, Medvedovski M, Goldsmith JR, Kordysh E (2001) A case-control study of Parkinson’s disease in urban population of southern Israel. Can J Neurol Sci 28:144–147

    PubMed  CAS  Google Scholar 

  • Herrera FE, Chesi A, Paleologou KE, Schmid A, Munoz A, Vendruscolo M, Gustincich S, Lashuel HA, Carloni P (2008) Inhibition of α-synuclein fibrillization by dopamine is mediated by interactions with five C-terminal residues and with E83 in the NAC region. PLoS ONE 3:e3394

    Article  PubMed  CAS  Google Scholar 

  • Hindle JV (2010) Ageing, neurodegeneration and Parkinson’s disease. Age Ageing 39:156–161

    Article  PubMed  Google Scholar 

  • Hubble JP, Cao T, Hassanein RES, Neuberger JS, Roller WC (1993) Risk factors for Parkinson’s disease. Neurology 43:1693–1697

    PubMed  CAS  Google Scholar 

  • Hung S-Y, Liou H-C, Kang K-H, Wu R-M, Wen C-C, Fu W-M (2008) Overexpression of heme oxygenase-1 protects dopaminergic neurons against 1-methyl-4-phenylpyridinium-induced neurotoxicity. Mol Pharmacol 74:1564–1575

    Article  PubMed  CAS  Google Scholar 

  • Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53:S26–S38

    Article  PubMed  CAS  Google Scholar 

  • Kang MJ, Gil SJ, Koh HC (2009) Paraquat induces alternation of the dopamine catabolic pathways and glutathione levels in the substantia nigra of mice. Toxicol Lett 188:148–152

    Article  PubMed  CAS  Google Scholar 

  • Kang MJ, Gil SJ, Lee JE, Koh HC (2010) Selective vulnerability of the striatal subregions of C57BL/6 mice to paraquat. Toxicol Lett 195:127–134

    Article  PubMed  CAS  Google Scholar 

  • Kempster PA, Hurwitz B, Lees AJ (2007) A new look at James Parkinson’s Essay on the Shaking Palsy. Neurology 69:482–485

    Article  PubMed  Google Scholar 

  • Kim ST, Choi JH, Chang JW, Kim SW, Hwang O (2005) Immobilization stress causes increases in tetrahydrobiopterin, dopamine, and neuromelanin and oxidative damage in the nigrostriatal system. J Neurochem 95:89–98

    Article  PubMed  CAS  Google Scholar 

  • Klein C, Schlossmacher MG (2007) Parkinson disease, 10 years after its genetic revolution: multiple clues to a complex disorder. Neurology 69:2093–2104

    Article  PubMed  Google Scholar 

  • Kostka M, Hogen T, Danzer KM, Levin J, Habeck M, Wirth A, Wagner R, Glabe CG, Finger S, Heinzelmann U, Garidel P, Duan W, Ross CA, Kretzschmar H, Giese A (2008) Single particle characterization of iron-induced pore-forming {alpha}-synuclein oligomers. J Biol Chem 283:10992–11003

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Lai BCL, Marion SA, Teschke K, Tsui JKC (2002) Occupational and environmental risk factors for Parkinson’s disease. Parkinsonism Relat Disord 8:297–309

    Article  PubMed  CAS  Google Scholar 

  • Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT Jr (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418:291

    Article  PubMed  CAS  Google Scholar 

  • LaVoie MJ, Hastings TG (1999) Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. J Neurosci 19:1484–1491

    PubMed  CAS  Google Scholar 

  • LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ (2005) Dopamine covalently modifies and functionally inactivates parkin. Nat Med 11:1214–1221

    Article  PubMed  CAS  Google Scholar 

  • Lees AJ, Hardy J, Revesz T (2009) Parkinson’s disease. Lancet 373:2055–2066

    Article  PubMed  CAS  Google Scholar 

  • Li H-T, Lin D-H, Luo X-Y, Zhang F, Ji L-N, Du H-N, Song G-Q, Hu J, Zhou J-W, Hu H-Y (2005) Inhibition of α-synuclein fibrillization by dopamine analogs via reaction with the amino groups of α-synuclein. FEBS J 272:3661–3672

    Article  PubMed  CAS  Google Scholar 

  • Lim C-S, Lee J-C, Kim SD, Chang D-J, Kaang B-K (2002) Hydrogen peroxide-induced cell death in cultured Aplysia sensory neurons. Brain Res 941:137–145

    Article  PubMed  CAS  Google Scholar 

  • Liou H, Tsai M, Chen C, Jeng J, Chang Y, Chen S, Chen R (1997) Environmental risk factors and Parkinson’s disease: a case-control study in Taiwan. Neurology 48:1583–1588

    PubMed  CAS  Google Scholar 

  • Liu B, Gao H-M, Hong J-S (2003) Parkinson’s disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: role of neuroinflammation. Environ Health Perspect 111:1065–1073

    Article  PubMed  CAS  Google Scholar 

  • Lotharius J, Brundin P (2002) Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3:932–942

    Article  PubMed  CAS  Google Scholar 

  • Luo Y, Henricksen LA, Giuliano RE, Prifti L, Callahan LM, Federoff HJ (2007) VIP is a transcriptional target of Nurr1 in dopaminergic cells. Exp Neurol 203:221–232

    Article  PubMed  CAS  Google Scholar 

  • Macianskiene R, Matejovic P, Sipido K, Flameng W, Mubagwa K (2001) Modulation of the extracellular divalent cation-inhibited non-selective conductance in cardiac cells by metabolic inhibition and by oxidants. J Mol Cell Cardiol 33:1371–1385

    Article  PubMed  CAS  Google Scholar 

  • Maguire-Zeiss KA, Federoff HJ (2003) Convergent pathobiologic model of Parkinson’s disease. Ann N Y Acad Sci 991:152–166

    Article  PubMed  CAS  Google Scholar 

  • Maguire-Zeiss KA, Short DW, Federoff HJ (2005) Synuclein, dopamine and oxidative stress: co-conspirators in Parkinson’s disease? Mol Brain Res 134:18–23

    Article  PubMed  CAS  Google Scholar 

  • Maguire-Zeiss KA, Wang CI, Yehling E, Sullivan MA, Short DW, Su X, Gouzer G, Henricksen LA, Wuertzer CA, Federoff HJ (2006) Identification of human [alpha]-synuclein specific single chain antibodies. Biochem Biophys Res Commun 349:1198–1205

    Article  PubMed  CAS  Google Scholar 

  • Mandel S, Grunblatt E, Riederer P, Amariglio N, Jacob-Hirsch J, Rechavi G, Youdim MBH (2005) Gene expression profiling of sporadic Parkinson’s disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKP1A, aldehyde dehydrogenase, and chaperone HSC-70. Ann N Y Acad Sci 1053:356–375

    Article  PubMed  CAS  Google Scholar 

  • Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of α-synuclein in mice. J Biol Chem 277:1641–1644

    Article  PubMed  CAS  Google Scholar 

  • Manning-Bog AB, McCormack AL, Purisai MG, Bolin LM, Di Monte DA (2003) Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci 23:3095–3099

    PubMed  CAS  Google Scholar 

  • Mariani E, Polidori MC, Cherubini A, Mecocci P (2005) Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview. J Chromatogr B 827:65–75

    Article  CAS  Google Scholar 

  • Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815

    PubMed  CAS  Google Scholar 

  • Mattson MP, Pedersen WA, Duan W, Culmsee C, Camandola S (1999) Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer’s and Parkinson’s diseases. Ann N Y Acad Sci 893:154–175

    Article  PubMed  CAS  Google Scholar 

  • Mazzulli JR, Mishizen AJ, Giasson BI, Lynch DR, Thomas SA, Nakashima A, Nagatsu T, Ota A, Ischiropoulos H (2006) Cytosolic catechols inhibit alpha-synuclein aggregation and facilitate the formation of intracellular soluble oligomeric intermediates. J Neurosci 26:10068–10078

    Article  PubMed  CAS  Google Scholar 

  • Mazzulli JR, Armakola M, Dumoulin M, Parastatidis I, Ischiropoulos H (2007) Cellular oligomerization of α-synuclein is determined by the interaction of oxidized catechols with a C-terminal sequence. J Biol Chem 282:31621–31630

    Article  PubMed  CAS  Google Scholar 

  • McCormack AL, Di Monte DA (2003) Effects of l-dopa and other amino acids against paraquat-induced nigrostriatal degeneration. J Neurochem 85:82–86

    Article  PubMed  CAS  Google Scholar 

  • McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, Di Monte DA (2002) Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 10:119–127

    Article  PubMed  CAS  Google Scholar 

  • McCormack AL, Atienza JG, Johnston LC, Andersen JK, Vu S, Di Monte DA (2005) Role of oxidative stress in paraquat-induced dopaminergic cell degeneration. J Neurochem 93:1030–1037

    Article  PubMed  CAS  Google Scholar 

  • McCormack AL, Atienza JG, Langston JW, Di Monte DA (2006) Decreased susceptibility to oxidative stress underlies the resistance of specific dopaminergic cell populations to paraquat-induced degeneration. Neuroscience 141:929–937

    Article  PubMed  CAS  Google Scholar 

  • Migliore L, Coppedè F (2009a) Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. Mutat Res 667:82–97

    PubMed  CAS  Google Scholar 

  • Migliore L, Coppedè F (2009b) Environmental-induced oxidative stress in neurodegenerative disorders and aging. Mutat Res 674:73–84

    PubMed  CAS  Google Scholar 

  • Miller R, James-Kracke M, Sun G, Sun A (2009) Oxidative and inflammatory pathways in Parkinson’s disease. Neurochem Res 34:55–65

    Article  PubMed  CAS  Google Scholar 

  • Mosharov EV, Larsen KE, Kanter E, Phillips KA, Wilson K, Schmitz Y, Krantz DE, Kobayashi K, Edwards RH, Sulzer D (2009) Interplay between cytosolic dopamine, calcium, and [alpha]-synuclein causes selective death of substantia nigra neurons. Neuron 62:218–229

    Article  PubMed  CAS  Google Scholar 

  • Moussa CEH, Mahmoodian F, Tomita Y, Sidhu A (2008) Dopamine differentially induces aggregation of A53T mutant and wild type alpha-synuclein: insights into the protein chemistry of Parkinson’s disease. Biochem Biophys Res Commun 365:833–839

    Article  PubMed  CAS  Google Scholar 

  • Murphy DD, Rueter SM, Trojanowski JQ, Lee VMY (2000) Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 20:3214–3220

    PubMed  CAS  Google Scholar 

  • Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH (2010) Increased expression of [alpha]-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65:66–79

    Article  PubMed  CAS  Google Scholar 

  • Norris EH, Giasson BI, Hodara R, Xu S, Trojanowski JQ, Ischiropoulos H, Lee VMY (2005) Reversible inhibition of α-synuclein fibrillization by dopaminochrome-mediated conformational alterations. J Biol Chem 280:21212–21219

    Article  PubMed  CAS  Google Scholar 

  • Norris EH, Uryu K, Leight S, Giasson BI, Trojanowski JQ, Lee VMY (2007) Pesticide exposure exacerbates [alpha]-synucleinopathy in an A53T transgenic mouse model. Am J Pathol 170:658–666

    Article  PubMed  CAS  Google Scholar 

  • Outeiro TF, Klucken J, Bercury K, Tetzlaff J, Putcha P, Oliveira LMA, Quintas A, McLean PJ, Hyman BT (2009) Dopamine-induced conformational changes in alpha-synuclein. PLoS ONE 4:e6906

    Article  PubMed  CAS  Google Scholar 

  • Paleologou KE, Oueslati A, Shakked G, Rospigliosi CC, Kim H-Y, Lamberto GR, Fernandez CO, Schmid A, Chegini F, Gai WP, Chiappe D, Moniatte M, Schneider BL, Aebischer P, Eliezer D, Zweckstetter M, Masliah E, Lashuel HA (2010) Phosphorylation at S87 is enhanced in synucleinopathies, inhibits {alpha}-synuclein oligomerization, and influences synuclein-membrane interactions. J Neurosci 30:3184–3198

    Article  PubMed  CAS  Google Scholar 

  • Pamplona R (2008) Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity. Biochim Biophys Acta Bioenergetics 1777:1249–1262

    Article  CAS  Google Scholar 

  • Papadimitriou A, Veletza V, Hadjigeorgiou GM, Patrikiou A, Hirano M, Anastasopoulos I (1999) Mutated {alpha}-synuclein gene in two Greek kindreds with familial PD: incomplete penetrance? Neurology 52:651–654

    PubMed  CAS  Google Scholar 

  • Peng J, Mao XO, Stevenson FF, Hsu M, Andersen JK (2004) The herbicide paraquat induces dopaminergic nigral apoptosis through sustained activation of the JNK pathway. J Biol Chem 279:32626–32632

    Article  PubMed  CAS  Google Scholar 

  • Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the {alpha}-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    Article  PubMed  CAS  Google Scholar 

  • Pountney DL, Lowe R, Quilty M, Vickers JC, Voelcker NH, Gai WP (2004) Annular α-synuclein species from purified multiple system atrophy inclusions. J Neurochem 90:502–512

    Article  PubMed  CAS  Google Scholar 

  • Prasad K, Winnik B, Thiruchelvam MJ, Buckley B, Mirochnitchenko O, Richfield EK (2007) Prolonged toxicokinetics and toxicodynamics of paraquat in mouse brain. Environ Health Perspect 115:1448–1453

    PubMed  CAS  Google Scholar 

  • Rajput A, Uitti R, Stern W, Laverty W, O’Donnell K, O’Donnell D, Yuen W, Dua A (1987) Geography, drinking water chemistry, pesticides and herbicides and the etiology of Parkinson’s disease. Can J Neurol Sci 14:414–418

    PubMed  CAS  Google Scholar 

  • Satake W et al (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet 41:1303–1307

    Article  PubMed  CAS  Google Scholar 

  • Schipper HM, Song W, Zukor H, Hascalovici JR, Zeligman D (2009) Heme oxygenase-1 and neurodegeneration: expanding frontiers of engagement. J Neurochem 110:469–485

    Article  PubMed  CAS  Google Scholar 

  • Schmuck G, Röhrdanz E, Tran-Thi Q, Kahl R, Schlüter G (2002) Oxidative stress in rat cortical neurons and astrocytes induced by paraquat in vitro. Neurotox Res 4:1–13

    Article  PubMed  CAS  Google Scholar 

  • Shtilerman MD, Ding TT, Lansbury PT (2002) Molecular crowding accelerates fibrillization of α-synuclein: could an increase in the cytoplasmic protein concentration induce Parkinson’s disease? Biochemistry 41:3855–3860

    Article  PubMed  CAS  Google Scholar 

  • Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD (1994) Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 36:348–355

    Article  PubMed  CAS  Google Scholar 

  • Simon-Sanchez J et al (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41:1308–1312

    Article  PubMed  CAS  Google Scholar 

  • Singleton AB et al (2003) Alpha-synuclein locus triplication causes Parkinson’s disease. Science 302:841

    Article  PubMed  CAS  Google Scholar 

  • Smith LL (1985) Paraquat toxicity. Philos Trans R Soc Lond B Biol Sci 311:647–657

    Article  PubMed  CAS  Google Scholar 

  • Smith CAD, Wolf CR, Gough AC, Spurr NK, Leigh PN, Summers BA, Harding AE, Maranganore DM, Sturman SG, Williams AC, Schapira AHV (1992) Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson’s disease. Lancet 339:1375–1377

    Article  PubMed  CAS  Google Scholar 

  • Song W, Patel A, Han D, Paudel HK, Schipper HM (2008) P2-136: heme oxygenase-1 promotes proteosomal degradation of tau and alpha-synuclein in human neuroblastoma cells. Alzheimer’s Dement 4:T410

    Article  Google Scholar 

  • Song W, Patel A, Qureshi HY, Han D, Schipper HM, Paudel HK (2009) The Parkinson disease-associated A30P mutation stabilizes α-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells. J Neurochem 110:719–733

    Article  PubMed  CAS  Google Scholar 

  • Spillantini MG, Schmidt ML, Lee VMY, Trojanowski JQ, Jakes R, Goedert M (1997) [Alpha]-synuclein in Lewy bodies. Nature 388:839–840

    Article  PubMed  CAS  Google Scholar 

  • Steidl JV, Gomez-Isla T, Mariash A, Ashe KH, Boland LM (2003) Altered short-term hippocampal synaptic plasticity in mutant [alpha]-synuclein transgenic mice. Neuroreport 14:219–223

    Article  PubMed  Google Scholar 

  • Strathdee CA, McLeod MR, Hall JR (1999) Efficient control of tetracycline-responsive gene expression from an autoregulated bi-directional expression vector. Gene 229:21–29

    Article  PubMed  CAS  Google Scholar 

  • Su X, Maguire-Zeiss KA, Giuliano R, Prifti L, Venkatesh K, Federoff HJ (2008) Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol Aging 29:1690–1701

    Article  PubMed  CAS  Google Scholar 

  • Sulzer D (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci 30:244–250

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Surmeier DJ, Guzman JN, Sanchez-Padilla J, Goldberg JA, Anders B, Cenci MA (2010b) What causes the death of dopaminergic neurons in Parkinson’s disease? Prog Brain Res 183:59–77

    Article  PubMed  CAS  Google Scholar 

  • Tanner CM (2010) Advances in environmental epidemiology. Mov Disord 25:S58–S62

    Article  PubMed  Google Scholar 

  • Thiruchelvam M, Brockel BJ, Richfield EK, Baggs RB, Cory-Slechta DA (2000) Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson’s disease? Brain Res 873:225–234

    Article  PubMed  CAS  Google Scholar 

  • Thiruchelvam MJ, Powers JM, Cory-Slechta DA, Richfield EK (2004) Risk factors for dopaminergic neuron loss in human α-synuclein transgenic mice. Eur J Neurosci 19:845–854

    Article  PubMed  CAS  Google Scholar 

  • Tsigelny IF, Bar-On P, Sharikov Y, Crews L, Hashimoto M, Miller MA, Keller SH, Platoshyn O, Yuan JXJ, Masliah E (2007) Dynamics of alpha-synuclein aggregation and inhibition of pore-like oligomer development by beta-synuclein. FEBS J 274:1862–1877

    Article  PubMed  CAS  Google Scholar 

  • Tsigelny IF, Sharikov Y, Miller MA, Masliah E (2008) Mechanism of alpha-synuclein oligomerization and membrane interaction: theoretical approach to unstructured proteins studies. Nanomedicine 4:350–357

    PubMed  CAS  Google Scholar 

  • Uversky VN (2007) Neuropathology, biochemistry, and biophysics of α-synuclein aggregation. J Neurochem 103:17–37

    PubMed  CAS  Google Scholar 

  • Uversky VN, Li J, Fink AL (2001a) Evidence for a partially folded intermediate in alpha-synuclein fibril formation. J Biol Chem 276:10737–10744

    Article  PubMed  CAS  Google Scholar 

  • Uversky VN, Li J, Fink AL (2001b) Pesticides directly accelerate the rate of [alpha]-synuclein fibril formation: a possible factor in Parkinson’s disease. FEBS Lett 500:105–108

    Article  PubMed  CAS  Google Scholar 

  • Uversky VN, Li J, Bower K, Fink AL (2002a) Synergistic effects of pesticides and metals on the fibrillation of [alpha]-synuclein: implications for Parkinson’s disease. Neurotoxicology 23:527–536

    Article  PubMed  CAS  Google Scholar 

  • Uversky VNM, Cooper E, Bower KS, Li J, Fink AL (2002b) Accelerated [alpha]-synuclein fibrillation in crowded milieu. FEBS Lett 515:99–103

    Article  PubMed  CAS  Google Scholar 

  • Volles MJ, Lee SJ, Rochet JC, Shtilerman MD, Ding TT, Kessler JC, Lansbury PT Jr (2001) Vesicle permeabilization by protofibrillar alpha-synuclein: implications for the pathogenesis and treatment of Parkinson’s disease. Biochemistry 40:7812–7819

    Article  PubMed  CAS  Google Scholar 

  • Weingarten P, Zhou QY (2001) Protection of intracellular dopamine cytotoxicity by dopamine disposition and metabolism factors. J Neurochem 77:776–785

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Kao S-Y, Lee FJS, Song W, Jin L-W, Yankner BA (2002) Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med 8:600–606

    Article  PubMed  CAS  Google Scholar 

  • Yumino K, Kawakami I, Tamura M, Hayashi T, Nakamura M (2002) Paraquat- and diquat-induced oxygen radical generation and lipid peroxidation in rat brain microsomes. J Biochem 131:565–570

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Zhou ZD, Yap BP, Gung AYT, Leong SM, Ang ST, Lim TM (2006) Dopamine-related and caspase-independent apoptosis in dopaminergic neurons induced by overexpression of human wild type or mutant alpha-synuclein. Exp Cell Res 312:156–170

    Article  PubMed  CAS  Google Scholar 

  • Zhou W, Gallagher A, Hong D-P, Long C, Fink AL, Uversky VN (2009) At low concentrations, 3,4-dihydroxyphenylacetic acid (DOPAC) binds non-covalently to [alpha]-synuclein and prevents its fibrillation. J Mol Biol 388:597–610

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Dr. Stefano Vicini for his generous help with electrophysiology and Dr. Howard Federoff for the MN9Dsyn cells. This study was supported by NIEHS (R01ES014470; KMZ).

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  1. Department of Neuroscience and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, 3970 Reservoir Rd NW, Washington, DC, 20057, USA

    Li Rebekah Feng & Kathleen A. Maguire-Zeiss

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Correspondence to Kathleen A. Maguire-Zeiss.

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Feng, L.R., Maguire-Zeiss, K.A. Dopamine and Paraquat Enhance α-Synuclein-Induced Alterations in Membrane Conductance. Neurotox Res 20, 387–401 (2011). https://doi.org/10.1007/s12640-011-9255-x

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  • DOI: https://doi.org/10.1007/s12640-011-9255-x

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