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. 2006 Apr 5;12(4):499–510. doi: 10.1111/j.1750-3639.2002.tb00468.x

Mechanistic Approaches to Parkinson's Disease Pathogenesis

Ranjita Betarbet 1,✉, Todd B Sherer 1, Donato A Di 2, J Timothy Greenamyre 1
PMCID: PMC8095781  PMID: 12408237

Abstract

Parkinson's disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration and development of cytoplasmic proteinaceous aggregates known as Lewy bodies. Although the pathogenic mechanisms responsible for PD are not completely understood, many clues have come from biochemical, epidemiological, and genetic studies. Mutations in certain genes found in rare, familial cases of PD, such as α‐synuclein and parkin, suggest a role for the ubiquitin‐proteosome system and aberrant protein aggregation. Biochemical analyses have implicated mitochondrial dysfunction in PD. Epidemiological and animal model studies point to a role for environmental toxins, some of which are mitochondrial inhibitors. Mitochondrial dysfunction, resulting from either genetic defects, environmental exposures or an interaction between the two, may cause α‐synuclein aggregation or neurodegeneration through oxidative stress or excitotoxicity. A better understanding of the mechanisms underlying PD should reveal novel therapeutic targets.

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References

  • 1. Alam ZI, Daniel SE, Lees AJ, Marsden DC, Jenner P, Halliwell B (1997) A generalised increase in protein carbonyls in the brain in Parkinson's but not incidental Lewy body disease. J Neurochem 69:1326–1329. [DOI] [PubMed] [Google Scholar]
  • 2. Albin RL, Greenamyre JT (1992) Alternative excitotoxic hypotheses. Neurology 42:733–738. [DOI] [PubMed] [Google Scholar]
  • 3. Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366–375. [DOI] [PubMed] [Google Scholar]
  • 4. Barbeau A, Cloutier T, Roy M, Plasse L, Paris S, Poirier J (1985) Ecogenetics of Parkinson's disease: 4‐hydroxylation of debrisoquine. Lancet 2:1213–1216. [DOI] [PubMed] [Google Scholar]
  • 5. Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271:C1424–1237. [DOI] [PubMed] [Google Scholar]
  • 6. Bennett MC, Bishop JF, Leng Y, Chock PB, Chase TN, Mouradian MM (1999) Degradation of alpha‐synuclein by proteasome. J Biol Chem 274:33855–33858. [DOI] [PubMed] [Google Scholar]
  • 7. Betarbet R, Sherer TB, MacKenzie G, Garcia‐Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3:1301–1306. [DOI] [PubMed] [Google Scholar]
  • 8. Bindoff LA, Birch‐Machin M, Cartlidge NE, Parker WD, Jr , Turnbull DM (1989) Mitochondrial function in Parkinson's disease [letter; comment]. Lancet 2:49. [DOI] [PubMed] [Google Scholar]
  • 9. Blandini F, Nappi G, Greenamyre JT (2001) Subthalamic infusion of an NMDA antagonist prevents basal ganglia metabolic changes and nigral degeneration in a rodent model of Parkinson's disease. Ann Neurol 49:525–529. [PubMed] [Google Scholar]
  • 10. Blin O, Desnuelle C, Rascol O, Borg M, Peyro Saint Paul H, Azulay JP, Bille F, Figarella D, Coulom F, Pellissier JF et al (1994) Mitochondrial respiratory failure in skeletal muscle from patients with Parkinson's disease and multiple system atrophy. J Neurol Sci 125:95–101. [DOI] [PubMed] [Google Scholar]
  • 11. Braak H, Braak E (2000) Pathoanatomy of Parkinson's disease. J Neurol 247 Suppl 2:II3–10. [DOI] [PubMed] [Google Scholar]
  • 12. Braak H, Braak E, Yilmazer D, Schultz C, De Vos RA, Jansen EN (1995) Nigral and extranigral pathology in Parkinson's disease. J Neural Transm Suppl 5:15–31. [PubMed] [Google Scholar]
  • 13. 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. [DOI] [PubMed] [Google Scholar]
  • 14. Cadet JL, Katz M, Jackson‐Lewis V, Fahn S (1989) Vitamin E attenuates the toxic effects of intrastriatal injection of 6‐ hydroxydopamine (6‐OHDA) in rats: behavioral and biochemical evidence. Brain Res 476:10–15. [DOI] [PubMed] [Google Scholar]
  • 15. Cardellach F, Marti MJ, Fernandez‐Sola J, Marin C, Hoek JB, Tolosa E, Urbano‐Marquez A (1993) Mitochondrial respiratory chain activity in skeletal muscle from patients with Parkinson's disease. Neurology 43:2258–2262. [DOI] [PubMed] [Google Scholar]
  • 16. Cassarino DS, Fall CP, Swerdlow RH, Smith TS, Halvorsen EM, Miller SW, Parks JP, Parker WD, Jr , Bennett JP, Jr. (1997) Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease. Biochim Biophys Acta 1362:77–86. [DOI] [PubMed] [Google Scholar]
  • 17. Chan DK, Woo J, Ho SC, Pang CP, Law LK, Ng PW, Hung WT, Kwok T, Hui E, Orr K, Leung MF, Kay R (1998) Genetic and environmental risk factors for Parkinson's disease in a Chinese population. J Neurol Neurosurg Psychiatry 65:781–784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Cleeter MW, Cooper JM, Schapira AH (1992) Irreversible inhibition of mitochondrial complex I by 1‐methyl‐4‐phenylpyridinium: evidence for free radical involvement. J Neurochem 58:786–789. [DOI] [PubMed] [Google Scholar]
  • 19. 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. [DOI] [PubMed] [Google Scholar]
  • 20. 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. [DOI] [PubMed] [Google Scholar]
  • 21. Crossman AR (1989) Neural mechanisms in disorders of movement. Comp Biochem Physiol A 93:141–149. [DOI] [PubMed] [Google Scholar]
  • 22. Degli Esposti M (1998) Inhibitors of NADH‐ubiquinone reductase: an overview. Biochim Biophys Acta 1364:222–235. [DOI] [PubMed] [Google Scholar]
  • 23. DeLong MR (1990) Primate models of movement disorders of basal ganglia origin. Trends Neurosci 13:281–285. [DOI] [PubMed] [Google Scholar]
  • 24. 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. [DOI] [PubMed] [Google Scholar]
  • 25. Farrer M, Chan P, Chen R, Tan L, Lincoln S, Hernandez D, Forno L, Gwinn‐Hardy K, Petrucelli L, Hussey J, Singleton A, Tanner C, Hardy J, Langston JW (2001) Lewy bodies and parkinsonism in families with parkin mutations. Ann Neurol 50:293–300. [DOI] [PubMed] [Google Scholar]
  • 26. Feany MB, Bender WW (2000) A Drosophila model of Parkinson's disease. Nature 404:394–398. [DOI] [PubMed] [Google Scholar]
  • 27. Floor E, Wetzel MG (1998) Increased protein oxidation in human substantia nigra pars compacta in comparison with basal ganglia and prefrontal cortex measured with an improved dinitrophenylhydrazine assay. Journal of Neurochemistry 70:268–275. [DOI] [PubMed] [Google Scholar]
  • 28. Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM (2000) Oxidative damage linked to neurodegeneration by selective alpha‐ synuclein nitration in synucleinopathy lesions. Science 290:985–989. [DOI] [PubMed] [Google Scholar]
  • 29. Golbe LI, Farrell TM, Davis PH (1990) Follow‐up study of early‐life protective and risk factors in Parkinsons disease. Mov Disord 5:66–70. [DOI] [PubMed] [Google Scholar]
  • 30. Good PF, Hsu A, Werner P, Perl DP, Olanow CW (1998) Protein nitration in Parkinson's disease. J Neuropathol Exp Neurol 57:338–342. [DOI] [PubMed] [Google Scholar]
  • 31. Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ (1998) The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living. Neurology 50:1346–1350. [DOI] [PubMed] [Google Scholar]
  • 32. Gorell JM, Rybicki BA, Cole Johnson C, Peterson EL (1999) Occupational metal exposures and the risk of Parkinson's disease. Neuroepidemiology 18:303–308. [DOI] [PubMed] [Google Scholar]
  • 33. Greenamyre JT (1993) Glutamate‐dopamine interactions in the basal ganglia: relationship to Parkinson's disease. J Neural Transm Gen Sect 91:255–269. [DOI] [PubMed] [Google Scholar]
  • 34. Greene JG, Greenamyre JT (1996) Bioenergetics and glutamate excitotoxicity. Prog Neurobiol 48:613–634. [DOI] [PubMed] [Google Scholar]
  • 35. Gu M, Cooper JM, Taanman JW, Schapira AH (1998) Mitochondrial DNA transmission of the mitochondrial defect in Parkinson's disease. Ann Neurol 44:177–186. [DOI] [PubMed] [Google Scholar]
  • 36. Hasegawa E, Takeshige K, Oishi T, Murai Y, Minakami S (1990) 1‐Methyl‐4‐phenylpyridinium (MPP+) induces NADH‐dependent superoxide formation and enhances NADH‐dependent lipid peroxidation in bovine heart sub‐mitochondrial particles. Biochem Biophys Res Commun 170:1049–1055. [DOI] [PubMed] [Google Scholar]
  • 37. Hattori N, Matsumine H, Asakawa S, Kitada T, Yoshino H, Elibol B, Brookes AJ, Yamamura Y, Kobayashi T, Wang M, Yoritaka A, Minoshima S, Shimizu N, Mizuno Y (1998) Point mutations (Thr240Arg and Gln311 Stop) [correction of Thr240Arg and Ala311Stop] in the Parkin gene [published erratum appears in Biochem Biophys Res Commun 1998 Oct 20; 251(2):666]. Biochem Biophys Res Commun 249:754–758. [DOI] [PubMed] [Google Scholar]
  • 38. Hensley K, Pye QN, Maidt ML, Stewart CA, Robinson KA, Jaffrey F, Floyd RA (1998) Interaction of alpha‐phenyl‐N‐tert‐butyl nitrone and alternative electron acceptors with complex I indicates a substrate reduction site upstream from the rotenone binding site. J Neurochem 71:2549–2557. [DOI] [PubMed] [Google Scholar]
  • 39. Hertzman C, Wiens M, Bowering D, Snow B, Calne D (1990) Parkinson's disease: a case‐control study of occupational and environmental risk factors. Am J Ind Med 17:349–355. [DOI] [PubMed] [Google Scholar]
  • 40. Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A, Mallory M, Wong J, Takenouchi T, Hashimoto M, Masliah E (2000) alpha‐synuclein promotes mitochondrial deficit and oxidative stress. American Journal of Pathology 157:401–410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Javitch JA, D'Amato RJ, Strittmatter SM, Snyder SH (1985) Parkinsonism‐inducing neurotoxin, N‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine: uptake of the metabolite N‐methyl‐4‐phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci U S A 82:2173–2177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Jenner P (1998) Oxidative mechanisms in nigral cell death in Parkinson's disease. Mov Disord 13:24–34. [PubMed] [Google Scholar]
  • 43. Jensen PH, Nielsen MS, Jakes R, Dotti CG, Goedert M (1998) Binding of alpha‐synuclein to brain vesicles is abolished by familial Parkinson's disease mutation. J Biol Chem 273:26292–26294. [DOI] [PubMed] [Google Scholar]
  • 44. Jha N, Jurma O, Lalli G, Liu Y, Pettus EH, Greenamyre JT, Liu RM, Forman HJ, Andersen JK (2000) Glutathione depletion in PC12 results in selective inhibition of mitochondrial complex I activity. Implications for Parkinson's disease. J Biol Chem 275:26096–260101. [DOI] [PubMed] [Google Scholar]
  • 45. Johnston JA, Ward CL, Kopito RR (1998) Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143:1883–1898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Kanda S, Bishop JF, Eglitis MA, Yang Y, Mouradian MM (2000) Enhanced vulnerability to oxidative stress by alpha‐synuclein mutations and C‐terminal truncation. Neuroscience 97:279–284. [DOI] [PubMed] [Google Scholar]
  • 47. 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 392:605–608. [DOI] [PubMed] [Google Scholar]
  • 48. Klockgether T, Turski L (1989) Excitatory amino acids and the basal ganglia: implications for the therapy of Parkinson's disease. Trends Neurosci 12:285–286. [DOI] [PubMed] [Google Scholar]
  • 49. Knoll J (1986) The pharmacology of (‐)deprenyl. J Neural Transm Suppl 5:75–89. [PubMed] [Google Scholar]
  • 50. Ko L, Mehta ND, Farrer M, Easson C, Hussey J, Yen S, Hardy J, Yen SH (2000) Sensitization of neuronal cells to oxidative stress with mutated human alpha‐synuclein [In Process Citation]. J Neurochem 75:2546–2554. [DOI] [PubMed] [Google Scholar]
  • 51. Kopito RR (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10:524–530. [DOI] [PubMed] [Google Scholar]
  • 52. Kumar R, Agarwal AK, Seth PK (1995) Free radical‐generated neurotoxicity of 6‐hydroxydopamine. J Neurochem 64:1703–1707. [DOI] [PubMed] [Google Scholar]
  • 53. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidineanalog synthesis. Science 219:979–980. [DOI] [PubMed] [Google Scholar]
  • 54. Lee HJ, Choi C, Lee SJ (2002(a)) Membrane‐bound alpha‐synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form. J Biol Chem 277:671–676. [DOI] [PubMed] [Google Scholar]
  • 55. Lee HJ, Shin SY, Choi C, Lee YH, Lee SJ (2002(b)) Formation and removal of alpha‐synuclein aggregates in cells exposed to mitochondrial inhibitors. J Biol Chem 277:5411–5417. [DOI] [PubMed] [Google Scholar]
  • 56. Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, Polymeropoulos MH (1998) The ubiquitin pathway in Parkinson's disease [letter]. Nature 395:451–452. [DOI] [PubMed] [Google Scholar]
  • 57. Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, Chen RC (1997) Environmental risk factors and Parkinson's disease: a case‐control study in Taiwan. Neurology 48:1583–1588. [DOI] [PubMed] [Google Scholar]
  • 58. Lopiano L, Fasano M, Giraudo S, Digilio G, Koenig SH, Torre E, Bergamasco B, Aime S (2000) Nuclear magnetic relaxation dispersion profiles of substantia nigra pars compacta in Parkinson's disease patients are consistent with protein aggregation. Neurochem Int 37:331–336. [DOI] [PubMed] [Google Scholar]
  • 59. Lotharius J, O'Malley KL (2000) The parkinsonism‐inducing drug 1‐methyl‐4‐phenylpyridinium triggers intracellular dopamine oxidation. A novel mechanism of toxicity. J Biol Chem 275:38581–38588. [DOI] [PubMed] [Google Scholar]
  • 60. Lucking CB, Abbas N, Durr A, Bonifati V, Bonnet AM, De Broucker T, De Michele G, Wood NW, Agid Y, Brice A (1998) Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinson's Disease and the French Parkinson's Disease Genetics Study Group [letter]. Lancet 352:1355–1356. [DOI] [PubMed] [Google Scholar]
  • 61. Lummen P (1998) Complex I inhibitors as insecticides and acaricides. Biochim Biophys Acta 1364:287–296. [DOI] [PubMed] [Google Scholar]
  • 62. Mann VM, Cooper JM, Krige D, Daniel SE, Schapira AH, Marsden CD (1992) Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson's disease. Brain 115:333–342. [DOI] [PubMed] [Google Scholar]
  • 63. Manning‐Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up‐regulation and aggregation of alpha‐synuclein in mice: paraquat and alpha‐synuclein. J Biol Chem 277:1641–1644. [DOI] [PubMed] [Google Scholar]
  • 64. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha‐synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269. [DOI] [PubMed] [Google Scholar]
  • 65. Matthews RT, Klivenyi P, Mueller G, Yang L, Wermer M, Thomas CE, Beal MF (1999) Novel free radical spin traps protect against malonate and MPTP neurotoxicity. Exp Neurol 157:120–126. [DOI] [PubMed] [Google Scholar]
  • 66. McNaught KS, Jenner P (2001) Proteasomal function is impaired in substantia nigra in Parkinson's disease. Neurosci Lett 297:191–194. [DOI] [PubMed] [Google Scholar]
  • 67. McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P (2001) Failure of the ubiquitin‐proteasome system in Parkinson's disease. Nat Rev Neurosci 2:589–594. [DOI] [PubMed] [Google Scholar]
  • 68. Menegon A, Board PG, Blackburn AC, Mellick GD, Le Couteur DG (1998) Parkinson's disease, pesticides, and glutathione transferase polymorphisms [see comments]. Lancet 352:1344–1346. [DOI] [PubMed] [Google Scholar]
  • 69. Mizuno Y, Yoshino H, Ikebe S, Hattori N, Kobayashi T, Shimoda‐Matsubayashi S, Matsumine H, Kondo T (1998) Mitochondrial dysfunction in Parkinson's disease. Ann Neurol 44:S99–109. [DOI] [PubMed] [Google Scholar]
  • 70. Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH‐linked oxidation in brain mitochondria by 1‐methyl‐4‐ phenyl‐pyridine, a metabolite of the neurotoxin, 1‐methyl‐4‐phenyl‐ 1,2,5,6‐tetrahydropyridine. Life Sci 36:2503–2508. [DOI] [PubMed] [Google Scholar]
  • 71. Parker WD, Jr. , Boyson SJ, Parks JK (1989) Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol 26:719–723. [DOI] [PubMed] [Google Scholar]
  • 72. Perumal AS, Gopal VB, Tordzro WK, Cooper TB, Cadet JL (1992) Vitamin E attenuates the toxic effects of 6‐hydrox‐ydopamine on free radical scavenging systems in rat brain. Brain Res Bull 29:699–701. [DOI] [PubMed] [Google Scholar]
  • 73. Piallat B, Benazzouz A, Benabid AL (1996) Subthalamic nucleus lesion in rats prevents dopaminergic nigral neuron degeneration after striatal 6‐OHDA injection: behavioural and immunohistochemical studies. Eur J Neurosci 8:1408–1414. [DOI] [PubMed] [Google Scholar]
  • 74. 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 [see comments]. Science 276:2045–2047. [DOI] [PubMed] [Google Scholar]
  • 75. Priyadarshi A, Khuder SA, Schaub EA, Priyadarshi SS (2001) Environmental risk factors and Parkinson's disease: a metaanalysis. Environ Res 86:122–127. [DOI] [PubMed] [Google Scholar]
  • 76. Priyadarshi A, Khuder SA, Schaub EA, Shrivastava S (2000) A meta‐analysis of Parkinson's disease and exposure to pesticides. Neurotoxicology 21:435–440. [PubMed] [Google Scholar]
  • 77. Reynolds IJ, Hastings TG (1995) Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J Neurosci 15:3318–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78. Sachs C, Jonsson G (1975) Mechanisms of action of 6‐hydroxydopamine. Biochem Pharmacol 24:1–8. [DOI] [PubMed] [Google Scholar]
  • 79. Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989) Mitochondrial complex I deficiency in Parkinson's disease [letter] [see comments]. Lancet 1:1269. [DOI] [PubMed] [Google Scholar]
  • 80. Schulz JB, Henshaw DR, Matthews RT, Beal MF (1995) Coenzyme Q10 and nicotinamide and a free radical spin trap protect against MPTP neurotoxicity. Exp Neurol 132:279–283. [DOI] [PubMed] [Google Scholar]
  • 81. Semchuk KM, Love EJ, Lee RG (1993) Parkinson's disease: a test of the multifactorial etiologic hypothesis. Neurology 43:1173–1180. [DOI] [PubMed] [Google Scholar]
  • 82. Sherer TB, Betarbet R, Stout AK, Lund S, Baptista M, Panov AV, Cookson MR, Greenamyre JT (2002) An in vitro model of Parkinson's Disease: Linking mitochondrial impairment to altered alpha‐synuclein metabolism and oxidative damage. J Neurosci 22:7006–7015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83. 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 25:302–305. [DOI] [PubMed] [Google Scholar]
  • 84. Shoffner JM, Watts RL, Juncos JL, Torroni A, Wallace DC (1991) Mitochondrial oxidative phosphorylation defects in Parkinson's disease [see comments]. Ann Neurol 30:332–339. [DOI] [PubMed] [Google Scholar]
  • 85. 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. [DOI] [PubMed] [Google Scholar]
  • 86. Souza JM, Giasson BI, Chen Q, Lee VM, Ischiropoulos H (2000) Dityrosine cross‐linking promotes formation of stable alpha ‐synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegen‐erative synucleinopathies. J Biol Chem 275:18344–18349. [DOI] [PubMed] [Google Scholar]
  • 87. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha‐synuclein in Lewy bodies [letter]. Nature 388:839–840. [DOI] [PubMed] [Google Scholar]
  • 88. Sriram K, Pai KS, Boyd MR, Ravindranath V (1997) Evidence for generation of oxidative stress in brain by MPTP: in vitro and in vivo studies in mice. Brain Res 749:44–52. [DOI] [PubMed] [Google Scholar]
  • 89. Stout AK, Raphael HM, Kanterewicz BI, Klann E, Reynolds IJ (1998) Glutamate‐induced neuron death requires mitochondrial calcium uptake. Nat Neurosci 1:366–373. [DOI] [PubMed] [Google Scholar]
  • 90. Swerdlow RH, Parks JK, Miller SW, Tuttle JB, Trimmer PA, Sheehan JP, Bennett JP, Jr , Davis RE, Parker WD, Jr (1996) Origin and functional consequences of the complex I defect in Parkinson's disease. Ann Neurol 40:663–671. [DOI] [PubMed] [Google Scholar]
  • 91. Tabrizi SJ, Orth M, Wilkinson JM, Taanman JW, Warner TT, Cooper JM, Schapira AH (2000) Expression of mutant alpha‐synuclein causes increased susceptibility to dopamine toxicity. Hum Mol Genet 9:2683–2689. [DOI] [PubMed] [Google Scholar]
  • 92. Takahashi RN, Rogerio R, Zanin M (1989) Maneb enhances MPTP neurotoxicity in mice. Res Commun Chem Pathol Pharmacol 66:167–170. [PubMed] [Google Scholar]
  • 93. Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory‐Slechta DA (2000) The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson's disease. J Neurosci 20:9207–9214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94. Tipton KF, Singer TP (1993) Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds. J Neurochem 61:1191–1206. [DOI] [PubMed] [Google Scholar]
  • 95. Turrens JF, Boveris A (1980) Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J 191:421–427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96. Uversky VN, Li J, Fink AL (2001) Pesticides directly accelerate the rate of alpha‐synuclein fibril formation: a possible factor in Parkinson's disease. FEBS Lett 500:105–108. [DOI] [PubMed] [Google Scholar]
  • 97. Van der Putten H, Wiederhold KH, Probst A, Barbieri S, Mistl C, Danner S, Kauffmann S, Hofele K, Spooren WP, Ruegg MA, Lin S, Caroni P, Sommer B, Tolnay M, Bilbe G (2000) Neuropathology in mice expressing human alphasynuclein. J Neurosci 20:6021–6029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98. Vila M, Vukosavic S, Jackson‐Lewis V, Neystat M, Jakowec M, Przedborski S (2000) Alpha‐synuclein upregulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP. J Neurochem 74:721–729. [DOI] [PubMed] [Google Scholar]
  • 99. Wigley WC, Fabunmi RP, Lee MG, Marino CR, Muallem S, DeMartino GN, Thomas PJ (1999) Dynamic association of proteasomal machinery with the centrosome. J Cell Biol 145:481–490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100. Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER, Mizuno Y (1996) Immunohistochemical detection of 4‐hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci U S A 93:2696–2701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101. Zou L, Xu J, Jankovic J, He Y, Appel SH, Le W (2000) Pramipexole inhibits lipid peroxidation and reduces injury in the substantia nigra induced by the dopaminergic neurotoxin 1‐methyl‐4‐ phenyl‐1,2,3,6‐tetrahydropyridine in C57BL/6 mice. Neurosci Lett 281:167–170. [DOI] [PubMed] [Google Scholar]

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