Skip to main content

Advertisement

Log in

Mitochondrial Dysfunction and Oxidative Stress in Parkinson’s Disease

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Environmental toxins, genetic predisposition and old age are major risk factors for Parkinson’s disease (PD). Although the mechanism(s) underlying selective dopaminergic (DA) neurodegeneration remain unclear, molecular studies in both toxin based models and genetic based models of the disease suggest a major etiologic role for mitochondrial dysfunction in the pathogenesis of PD. Further, recent studies have presented clear evidence for a high burden of mtDNA deletions within the substantia nigra neurons in individuals with PD. Ultimately, an understanding of the molecular events which precipitate DA neurodegeneration in idiopathic PD will enable the development of targeted and effective therapeutic strategies. We review recent advances and current understanding of the genetic factors, molecular mechanisms and animal models of PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Abou-Sleiman P, Muqit M, Wood N (2006) Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci 7:207–219

    PubMed  CAS  Google Scholar 

  2. Alam Z, Daniel S, Lees A, Marsden D, 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

    Article  PubMed  CAS  Google Scholar 

  3. Allan S, Rothwell N (2001) Cytokines and acute neurodegeneration. Nat Rev Neurosci 2:734–744

    PubMed  CAS  Google Scholar 

  4. Arimoto T, Bing G (2003) Up-regulation of inducible nitric oxide synthase in the substantia nigra by lipopolysaccharide causes microglial activation and neurodegeneration. Neurobiol Dis 12:35–45

    PubMed  CAS  Google Scholar 

  5. Arimoto T, Choi D, Lu X, Liu M, Nguyen X, Zheng N, Stewart C, Kim H, Bing G (2006) Interleukin-10 protects against inflammation-mediated degeneration of dopaminergic neurons in substantia nigra. Neurobiol Aging 28:894–906

    Google Scholar 

  6. Banati R, Gehrmann J, Schubert P, Kreutzberg GW (1993) Cytotoxicity of microglia. Glia 7:111–118

    PubMed  CAS  Google Scholar 

  7. Beal M (2003) Bioenergetic approaches for neuroprotection in Parkinson’s disease. Ann Neurol 53:S39–S47

    PubMed  CAS  Google Scholar 

  8. Beal M (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58:495–505

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  10. Berger J, Glitza I (2003) Von’s Economo’s Encephalitis. In: Nath A Jr. (ed) Clinical neurovirology. Marcel Dekker, New York, p 523–542

    Google Scholar 

  11. Betarbet R, Sherer T, MacKenzie G, Garcia-Osuna M, Panov A, Greenamyre J (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nature Neurosci 3:1301–1306

    PubMed  CAS  Google Scholar 

  12. Biglan K, Ravina B (2007) Neuroprotection in Parkinson’s disease: an elusive goal. Semin Neurol 27:106–112

    PubMed  Google Scholar 

  13. Blum D, Wu Y, Nissou M, Arnaud S, Benabid AL, Verna JM (1997) P53 and bax activation in 6-hydroxydopamine-induced apoptosis in PC12 cells. Brain Res 751:139–142

    PubMed  CAS  Google Scholar 

  14. Bossy Wetzel E, Schwarzenbacher R, Lipton S (2004) Molecular pathways to neurodegeneration. Nat Med 10:S2–S9

    PubMed  Google Scholar 

  15. Casali C, Bonifati V, Santorelli F, Casari G, Fortini D, Patrignani A, Fabbrini G, Carrozzo R, D’Amati G, Locuratolo N, Vanacore N, Damiano M, Pierallini A, Pierelli F, Amabile G, Meco G (2001) Mitochondrial myopathy, parkinsonism, and multiple mtDNA deletions in a Sephardic Jewish family. Neurology 56:802–805

    PubMed  CAS  Google Scholar 

  16. Casals J, Elizan T, Yahr M (1998) Postencephalitic parkinsonism—a review. J Neural Transm 105:645–676

    PubMed  CAS  Google Scholar 

  17. Casetta I, Govoni V, Granieri E (2005) Oxidative stress, antioxidants and neurodegenerative diseases. Curr Pharm Des 11:2033–2052

    PubMed  CAS  Google Scholar 

  18. Cassarino DS, Halvorsen EM, Swerdlow RH, Abramova NN, Parker WD Jr, Sturgill TW, Bennett JP Jr (2000) Interaction among mitochondria, mitogen-activated protein kinases, and nuclear factor-kappaB in cellular models of Parkinson's disease. J Neurochem 74(4):1384–1392

    PubMed  CAS  Google Scholar 

  19. Castano A, Herrera A, Cano J, Machado A (1998) Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system. J Neurochem 70:1584–1592

    Article  PubMed  CAS  Google Scholar 

  20. Chalmers R, Brockington M, Howard R, Lecky B, Morgan-Hughes J, Harding A (1996) Mitochondrial encephalopathy with multiple mitochondrial DNA deletions: a report of two families and two sporadic cases with unusual clinical and neuropathological features. J Neurol Sci 143:41–45

    PubMed  CAS  Google Scholar 

  21. Chen H, Zhang S, Hernan M, Schwartzschild M, Willett W, Colditz G, Speizer F, Ascherio A (2003) Nonsteriodal anti-inflammatory drugs and the risk of Parkinson's disease. Arch Neurol 60:1059–1064

    PubMed  Google Scholar 

  22. Chen L, Thiruchelvam M, Madura K, Richfield E (2006) Proteasome dysfunction in aged human alpha-synuclein transgenic mice. Neurobiol Dis 23:120–126

    PubMed  CAS  Google Scholar 

  23. Chiueh C, Haung S, Murphy D (1992) Enhanced hydroxyl radical generation by 2′-methyl analog of MPTP: suppression by clorgyline and deprenyl. Synapse 11:346–348

    PubMed  CAS  Google Scholar 

  24. Chu C, Levinthal D, Kulich S, Chalovich E, DeFranco D (2004) Oxidative neuronal injury: the dark side of ERK1/2. Eur J Biochem 271:2060–2066

    PubMed  CAS  Google Scholar 

  25. Chu C, Zhu J-H (2003) Subcellular compartmentalization of P-ERKs in the Lewy body disease substantia nigra. Ann NY Acad Sci 991:288–290

    Article  Google Scholar 

  26. Ciccetti F, Brownell A, Williams K, Chen Y, Livni E, Isacson O (2002) Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci 15:991–998

    Google Scholar 

  27. Clark I, Dodson M, Jiang C, Cao J, Huh J, Seol J, Yoo S, Hay Ba, Guo M (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166

    PubMed  CAS  Google Scholar 

  28. Coelln R, Kugler S, Bahr M, Weller M, Dichgans J, Schulz J (2001) Rescue from death but not from functional impairment: caspase inhibition protects dopaminergic cells against 6-hydroxydopamine induced apoptosis but not against the loss of their terminals. J Neurochem 77:263–273

    Article  Google Scholar 

  29. Cooper J, Daniel S, Marsden C, Schapira A (1995) L-dihydroxyphenylalanine and complex I deficiency in Parkinson’s disease brain. Mov Disord 10:295–297

    PubMed  CAS  Google Scholar 

  30. Crouser E, Julian M, Blaho D, Pfeiffer D (2002) Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med 30:276–284

    PubMed  CAS  Google Scholar 

  31. Czlonkowska A, Kohuknika M, Kurkowska-Jatrzebska I, Czlonkowski A (1996) Microglial reaction in MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson's disease mice model. Neurodegeneration 5:137–143

    PubMed  CAS  Google Scholar 

  32. Darios F, Corti O, Lucking C, Hampe C, Muriel M, Abbas N, Gu W, Hirsch E, Rooney T, Ruberg M, Brice A (2003) Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum Mol Genet 12:517–526

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  34. De Coo I, Renier W, Ruitenbeek W, Ter Laak H, Bakker M, Schagger H, Van Oost B, Smeets H (1999) A 4-base pair deletion in the mitochondrial cytochrome b gene associated with Parkinsonism/MELAS overlap syndrome. Ann Neurol 45:130–133

    PubMed  Google Scholar 

  35. de Lau L, Breteler M (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5:525–535

    PubMed  Google Scholar 

  36. Dexter D, Wells F, Agid F, Agid Y, Lees AJ, Jenner P, Marsden CD (1987) Increased nigral iron content in postmortem parkinsonian brain. Lancet 8569:1219–1220

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  38. Elkon H, Melamed E, Offen D (2004) Oxidative stress, induced by 6-hydroxydopamine, reduces proteasome activities in PC12 cells: implications for the pathogenesis of Parkinson’s disease. J Mol Neurosci 24:387–400

    PubMed  CAS  Google Scholar 

  39. Fall CP, Bennett JP Jr (1999) Visualization of cyclosporin A and Ca2+-sensitive cyclical mitochondrial depolarizations in cell culture. Biochim Biophys Acta 1410(1):77–84

    PubMed  CAS  Google Scholar 

  40. Feng Z, Wang T, Li D, Fung P, Wilson B, Liu B, Ali S, Langenbach R, Hong J (2002) Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4-phenyl-1,2,3,6-tetradydropyridine-induced damage of dopaminergic neurons in the substantia nigra. Neurosci Lett 329:354–358

    PubMed  CAS  Google Scholar 

  41. Fisher J, Mizrahi T, Schori H, Yoles E, Levkovitch-Verbin H, Haggaig S, Revel M, Schwartz M (2001) Increased post-traumatic survival of neurons in IL-6-knockout mice on a background of EAE susceptibility. J Neuroimmunol 119:1–9

    PubMed  CAS  Google Scholar 

  42. Friedlander R (2003) Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 348:1365–1375

    PubMed  CAS  Google Scholar 

  43. Gao H, Hong J, Zhang W, Liu B (2002) Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J Neurosci 22:782–790

    PubMed  CAS  Google Scholar 

  44. Gao H, Liu B, Zhang W, Hong J (2003) Synergistic dopaminergic neurotoxicity of MPTP and inflammogen lipopolysaccharide: relevance to the etioloy of Parkinson's disease. FASEB J 17:1957–1971

    PubMed  CAS  Google Scholar 

  45. Gayle D, Ling Z, Tong C, Landers T, Lipton J, Carvey P (2002) Lipopolysacchride (LPS)-induced dopamine cell loss in culture: roles of tumor necrosis factor-alpha, interleukin-1beta, and nitric oxide. Brain Res Dev 133:27–35

    CAS  Google Scholar 

  46. Ghee M, Fournier A, Mallet J (2000) Rat alpha-synuclein interacts with Tat binding protein 1, a component of the 26S proteasomal complex. J Neurochem 75:2221–2224

    PubMed  CAS  Google Scholar 

  47. Gomez-Santos C, Ferrer I, Reiriz J, Vinals F, Barrachina M, Ambrosio S (2002) MPP+ increases α-synuclein expression and ERK/MAP-kinase phosphorylation in human neuroblastoma SH-SY5Y cells. Brain Res 935:32–39

    PubMed  CAS  Google Scholar 

  48. Gu M, Cooper J, Taanman J, Schapira A (1998) Mitochondrial DNA transmission of the mitochondrial defect in Parkinson’s disease. Ann Neurol 44:177–186

    PubMed  CAS  Google Scholar 

  49. Gu Z, Nakamura T, Yao D, Shi Z, Lipton S (2005) S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Cell Death Differ 12:1202–1204

    PubMed  CAS  Google Scholar 

  50. Hald A, Lotharius J (2005) Oxidative stress and inflammation in Parkinson’s disease: is there a casual link? Exp Neurol 193:279–190

    PubMed  CAS  Google Scholar 

  51. Halliwell B, Gutteridge J (1999) Oxidative stress in PD. In: Halliwell B, Gutteridge J (eds) Free radicals in biology and medicine. Oxford University Press, New York pp 744–758

    Google Scholar 

  52. Hartley A, Stone J, Heron C, Cooper J, Schapira A (1994) Complex I inhibitors induce dose-dependent apoptosis in PC12 cells: relevance to Parkinson’s disease. J Neurochem 63:1987–1990

    Article  PubMed  CAS  Google Scholar 

  53. Hartmann A, Hunot S, Michel PP, Muriel MP, Vyas S, Faucheux BA, Mouatt-Prigent A, Turmel H, Srinivasan A, Ruberg M, Evan GI, Agid Y, Hirsch EC (2000) Caspase-3: a vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc Natl Acad Sci USA 97(6):2875–2880

    PubMed  CAS  Google Scholar 

  54. Hattori N, Tanaka M, Ozawa T, Mizuno Y (1991) Immunohistochemical studies on complexes I, II, III, IV of mitochondria in Parkinson’s disease. Ann Neurol 30:563–571

    PubMed  CAS  Google Scholar 

  55. He Y, Appel S, Le W (2001) Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res 909:187–193

    Google Scholar 

  56. Hemmer K, Fransen I, Vanderstichele H, VanmeChelen E, Heuschling P (2001) An in vitro model for the study of microglial-induced neurodegeneration: involvement of nitric oxide and tumour necrosis factor-alpha. Neurochem Int 38:557–565

    PubMed  CAS  Google Scholar 

  57. Hererra A, Castano A, Venero J, Cano J, Machado A (2000) The single intranigral injection of LPS as a new model for studying the selective effects of inflammatory reactions on dopaminergic system. Neuorobiol Dis 7:429–447

    Google Scholar 

  58. Hirsh E, Hunot S, Damier P, Faucheux B (1998) Glial cells and inflammation in Parkinson's disease: a role in neurodegeneration? . Ann Neurol 44:S115–S120

    Google Scholar 

  59. Hunter R, Dragicevic N, Seifert K, Choi D, Liu M, Kim H, Cass W, Sullivan P, Bing G (2007) Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem 100:1375–1386

    PubMed  CAS  Google Scholar 

  60. Iravani M, Kashell K, Rose S, Jenner P (2002) Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration. Neuroscience 110:49–58

    PubMed  CAS  Google Scholar 

  61. Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53(Suppl 3):S26–S36

    PubMed  CAS  Google Scholar 

  62. Junn E, Mouradian M (2001) Apoptotic signaling in dopamine-induced cell death: the role of oxidative stress, p38 mitogen activated protein kinase, cytochrome c and caspases. J Neurochem 78:374–383

    PubMed  CAS  Google Scholar 

  63. Keeny P, Xie J, Capaldi R, Bennett J Jr (2006) Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits, is functionally impaired and misassembled. J Neurosci Res 26:5256–5264

    Google Scholar 

  64. Kim R, Peters M, Jang Y, Shi W, Pintilie M, Fletcher G, DeLuca C, Liepa J, Zhou L, Snow B, Binari R, Manoukian A, Bray M, Liu F, Tsao M, Mak T (2005) DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7:263–273

    PubMed  CAS  Google Scholar 

  65. Kim S, Kong P, Kim B, Sheen D, Nam S, Chun W (2004) Inhibitory action of minocycline on lipopolysaccharide-induced release of nitric oxide and prostaglandin E2 in BV2 microglial cells. Arch Pharm Res 27:314–318

    Article  PubMed  CAS  Google Scholar 

  66. Kitamura Y, Kosaka T, Kakimura J, Matsouka Y, Nomura Y, Tan-guchi T (1998) Protective effects of the antiparkinsonian drugs talipexole and pramipexole against 1-methyl 4-phenylpyridinium-induced apoptotic death in human neuroblastoma SH-SY5Y cells. Mol Pharmacol 54:1046–1054

    PubMed  CAS  Google Scholar 

  67. Kraytsberg Y, Kudryavtseva E, McKee A, Geula C, Kowall N, Khrapko K (2006) Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 38:507–508

    Google Scholar 

  68. Kulich S, Chu C (2003) Role of reactive oxygen species in ERK phosphorylation and 6-hydroxydopamine cytotoxicity. J Biosci 28:83–89

    PubMed  CAS  Google Scholar 

  69. Kulich S, Chu C (2001) Sustained extracellular signal-regulated kinase activation by 6-hydroxydopamine: implications for Parkinson’s disease. J Neurochem 77:1058–1066

    PubMed  CAS  Google Scholar 

  70. Kulisz A, Chen N, Chandel N, Shao Z, Schumacker P (2002) Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes. Am J Physiol Lung Cell Mol Physiol 282:L1324–L1329

    PubMed  CAS  Google Scholar 

  71. Kuroda Y, Mitsui T, Kunishige M, Matsumoto T (2006) Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet 15:883–895

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  73. Le W, Rowe D, Xie W, Ortiz I, He Y, Appel S (2001) Microglial activation and dopaminergic cell injury: an in vitro model relevant to Parkinson’s disease. J Neurosci Res 21:8447–8455

    CAS  Google Scholar 

  74. Liberatore G, Jackson-Lewis V, Vukosavic S, Mandir A, Vila M, McAuliffe W, Dawson V, Dawson T, Przedborski S (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson’s. Nat Med 5:1403–1409

    PubMed  CAS  Google Scholar 

  75. Lin M, Beal M (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    PubMed  CAS  Google Scholar 

  76. Lindersson E, Beedholms R, Hojrup P, Moos T, Gai W, Gendil K, Jensen P (2004) Proteasomal inhibition by α-synuclein filaments and oligomers. J Biol Chem 279:12924–12934

    PubMed  CAS  Google Scholar 

  77. Liu B, Gao H, Wang J, Jeohn GH, Cooper CL, Hong JS (2002) Role of nitric oxide in inflammation-mediated neurodegeneration. Ann NY Acad Sci 991:80–92

    Google Scholar 

  78. Liu B, Jiang J, Wilson B, Du L, Yang S, Wang JY, Wu G, Cao X, Hong J (2000) Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide. J Pharmacol Exp Ther 295:125–132

    PubMed  CAS  Google Scholar 

  79. Liu Y, Qin L, Li G, Zhang W, An L, Liu B (2003) Dextromethorplan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J Pharmacol Exp Ther 305:212–218

    PubMed  CAS  Google Scholar 

  80. Lu X, Bing G, Hagg T (2000) Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats. Neuroscience 97:285–291

    PubMed  CAS  Google Scholar 

  81. Ma J, Ma J (2002) The dual effect of the particulate and organic components of diesel exhaust particles on the alteration of pulmonary immune/inflammatory responses and metabolic enzymes. J Environ Carcinog Ecotoxicol Rev 20:117–147

    Google Scholar 

  82. Maguire-Zeiss K, Federoff H (2003) Convergent pathobiologic model of Parkinson’s disease. Ann NY Acad Sci 991:152–166

    Article  PubMed  CAS  Google Scholar 

  83. McGeer P, Yasojima K, McGeer E (2001) Inflammation in Parkinson’s disease. Adv Neurol 86:83–89

    PubMed  CAS  Google Scholar 

  84. Menzies F, Yenisetti S, Min K-T (2005) Roles of Drosophila DJ-1 in survival of dopaminergic neurons and oxidative stress. Curr Biol 15:1578–1582

    PubMed  CAS  Google Scholar 

  85. Meulener M, Whitworth AJ, Armstrong-Gold C, Rizzu P, Heutink P, Wes P, Pallanck L, Bonini N (2005) Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson’s disease. Curr Biol 15:1572–1577

    PubMed  CAS  Google Scholar 

  86. Minghetti L, Levi G (1998) Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Prog Neurobiol 54:99–125

    PubMed  CAS  Google Scholar 

  87. Moore D, West A, Dawson V, Dawson T (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87

    PubMed  CAS  Google Scholar 

  88. Nagatsu T, Mogi M, Ichinose H, Togari A (2000) Changes in cytokines and neurotrophins in Parkinson’s disease. J Neural Transm Suppl 60:277–290

    PubMed  Google Scholar 

  89. Nemoto S, Takeda K, Yu Z, Ferrans V, Finkel T (2000) Role for mitochondrial oxidants as regulators of cellular metabolism. Mol Cell Biol 20:7311–7318

    PubMed  CAS  Google Scholar 

  90. Niehaus I (2004) Lipopolysaccharides induce inflammation-mediated neurodegeneration in the substantia nigra and cerebral cortex (a case report). In: Hanin I, Cacabelos R (eds) New trends in Alzheimer and Parkinson related disorders. Monduzzi Editore, Bologna, pp 36–39

    Google Scholar 

  91. Olanow C, McNaught K (2006) Ubiquitin-proteasome system and Parkinson’s disease. Mov Disord 21:1806–1823

    PubMed  Google Scholar 

  92. Onyango IG, Tuttle JB, Bennett JP Jr (2005) Brain derived growth factor and Glial cell line-derived growth factor have different survival promoting effects and use distinct intracellular signaling pathways to protect PD cybrids from H2O2 induced apoptotic death. Neurobiol Dis 20:141–154

    PubMed  CAS  Google Scholar 

  93. Onyango IG, Tuttle JB, Bennett Jr JP (2005) Activation of p38 and N-acetyl cycteine sensitive c-Jun NH2-terminal kinase signaling cascades is required for induction of apoptosis in Parkinson’s disease cybrids. Mol Cell Neurosci 28(3):452–461

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  95. Parker WD Jr, Boyson SJ, Parks JK (2007) Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 26(6):719–723

    Google Scholar 

  96. Perier C, Bove J, Wu DC, Dehay B, Choi DK, Jackson-Lewis V, Rathke-Hartlieb S, Bouillet P, Strasser A, Schulz JB, Przedborski S, Vila M (2007) Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson’s disease. Proc Natl Acad Sci USA 104:8161–8166

    PubMed  CAS  Google Scholar 

  97. Petit A, Kawarai T, Paitel E, Sanjo N, Maj M, Scheid M, Chen F, Gu Y, Hasegawa H, Salehi-Rad S, Wang L, Rogaeva E, Fraser P, Robinson B, St George-Hyslop P, Tandon A (2005) Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J Biol Chem 280:34025–34032

    PubMed  CAS  Google Scholar 

  98. Petrovitch H, Ross GW, Abbott R, Sanderson W, Sharp D, Tanner C, Masaki K, Blanchette P, Popper J, Foley D, Launer L, White L (2002) Plantation work and risk of Parkinson disease in a population-based longitudinal study. Arch Neurol 59:1787–1792

    PubMed  Google Scholar 

  99. Schapira A (2006) Etiology of Parkinson’s disease. Neurology 66:S10–S23

    PubMed  Google Scholar 

  100. Schapira A (2006) Mitochondrial disease. Lancet 368:70–82

    PubMed  CAS  Google Scholar 

  101. Schapira A, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD (1990) Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 54:823–827

    PubMed  CAS  Google Scholar 

  102. Shen J, Cookson M (2004) Mitochondria and dopamine: new insights into recessive parkinsonism. Neuron 43:301–304

    PubMed  CAS  Google Scholar 

  103. Sherer T, Betarbet R, Greenamyre J (2002) Environment, mitochondria, and Parkinson’s disease. Neuroscientist 8:192–197

    PubMed  CAS  Google Scholar 

  104. Sherer T, Betarbet R, Stout AK, Lund S, Baptista M, Panov A, Cookson M, Greenamyre J (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

    PubMed  CAS  Google Scholar 

  105. Sian J, Dexter D, Jenner P, Marsden C (1991) Decreased in nigral glutathione in Parkinson’s disease. Br J Pharmacol 104:281

    Google Scholar 

  106. Siciliano G, Mancuso M, Ceravolo R, Lombardi V, Iudice A, Bonuccelli U (2001) Mitochondrial DNA rearrangements in young onset parkinsonism: two case reports. J Neurol Neurosurg Psychiat 71:685–687

    PubMed  CAS  Google Scholar 

  107. Silvestri L, Caputo V, Bellacchio E, Atorino L, Dallapiccola B, Valente E, Casari G (2005) Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet 14:3477–3492

    PubMed  CAS  Google Scholar 

  108. Singh M, Patel S, Dikshit M, Gupta Y (2006) Contribution of genomics and proteomics in understanding the role of modifying factors in Parkinson’s disease. Indian J Biochem Biophys 43:69–81

    PubMed  CAS  Google Scholar 

  109. Smeyne R, Jackson-Lewis V (2005) The MPTP model of Parkinson’s disease. Brain Res Mol Brain Res 134:57–66

    PubMed  CAS  Google Scholar 

  110. Smigrodzki R, Parks J, Parker W (2004) High frequency of mitochondrial complex I mutations in Parkinson’s disease and aging. Neurobiol Aging 25:1273–1281

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  112. Sriram K, Matheson J, Benkovic S, Miller D, Luster M, O’Callaghan J (2002) Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson’s disease. FASEB J 16:474–476

    Google Scholar 

  113. Strauss K, Martins L, Plun-Favreau H, Marx F, Kautzmann S, Berg D, Gasser T, Wszolek Z, Muller T, Bornemann A, Wolburg H, Downward J, Riess O, Schulz J, Kruger R (2005) Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet 14:2099–2111

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  115. Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R (2001) A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol cell Neurosci 8:613–621

    CAS  Google Scholar 

  116. 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(4):663–671

    PubMed  CAS  Google Scholar 

  117. Takai N, Nakanishi H, Tanabe K, Nishioku T, Sugiyama T, Fujiwara M, Yamamoto K (1998) Involvement of caspase-like pin apoptosis of neural PC12 cells and primary cultures microglia induced by 6-hydroxydopamine. J Neurosci Res 54:214–222

    PubMed  CAS  Google Scholar 

  118. Teismann P, Tieu K, Cohen O, Choi D, Wu D, Marks D, Vila M, Jackson-Lewis V, Przedborski S (2003) Pathologic role of glial cells in Parkinson’s disease. Movement Dis 18:121–129

    PubMed  Google Scholar 

  119. Teismann P, Vila M, Choi D, Tieu K, Wu D, Jackson-Lewis V, Przedborski S (2003) Cylooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. Proc Natl Acad Sci USA 100:5473–5478

    PubMed  CAS  Google Scholar 

  120. Thyagarajan D, Bressman S, Bruno C, Przedborski S, Shanske S, Lynch T, Fahn S, DiMauro S (2000) A novel mitochondrial 12S rRNA point mutation in Parkinsonism, deafness and neuropathy. Ann Neurol 48:730–736

    PubMed  CAS  Google Scholar 

  121. Trifunovic A, Hansson A, Wredenberg A, Rovio A, Dufour E, Khvorostov I, Spelbrink J, Wibom R, Jacobs H, Larsson N (2005) Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc Natl Acad Sci USA 102:17993–17998

    PubMed  CAS  Google Scholar 

  122. Trimmer PA, Borland MK, Keeney PM, Bennett JP Jr, Parker WD Jr (2004) Parkinson’s disease transgenic mitochondrial cybrids generate Lewy inclusion bodies. J Neurochem 88(4):800–812

    Article  PubMed  CAS  Google Scholar 

  123. van der Walt J, Nicodemus K, Martin E, Scott W, Nance M, Watts R, Hubble J, Haines J, Koller W, Lyons K, Pahwa R, Stern M, Colcher A, Hiner B, Jankovic J, Ondo W, Allen FJ, Goetz C, Small G, Mastaglia F, Stajich J, McLaurin A, Middleton L, Scott B, Schmechel D, Pericak-Vance M, Vance J (2003) Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet 72:804–811

    PubMed  Google Scholar 

  124. Vijitruth R, Liu M, Choi D, Nguyen X, Hunter R, Bing G (2006) Cyclooxygenase-2 mediates microglial activation and secondary dopaminergic cell death in the mouse MPTP model of Parkinson’s disease. J Neuroinflammation 3:1742–2094

    Google Scholar 

  125. von Bohlen und Halbach O, Schober A, Krieglstein K (2004) Genes, proteins, and neurotoxins involved in Parkinson’s disease. Prog Neurobiol 73:151–177

    Google Scholar 

  126. Waragai M, Wei J, Fujita M, Nakai M, Ho G, Masliah E, Akatsu H, Yamada T, Hashimoto M (2006) Increased level of DJ-1 in the cerebrospinal fluids of sporadic Parkinson's disease. Biochem Biophys Res Commun 345(3):967–972

    PubMed  CAS  Google Scholar 

  127. Welty-Wolf K, Simonson S, Huang Y, Fracica P, Patterson J, Piantadosi C (1996) Ultrastructural changes in skeletal muscle mitochondria in Gram-negative sepsis. Shock 5:378–384

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  129. Wood-Kaczmar A, Gandhi S, Wood N (2006) Understanding the molecular causes of Parkinson’s disease. Trends Mol Med 12:521–528

    PubMed  CAS  Google Scholar 

  130. Wu D, Teismann P, Tieu K, Vila M, Jackson-Lewis V, Ischiropoulos H, Przedborski S (2003) NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Proc Natl Acad Sci USA 100:6145–6150

    PubMed  CAS  Google Scholar 

  131. Xie Z, Smith C, Van Eldik L (2004) Activated glia induce neuron death via MAP kinase signaling pathways involving JNK and p38. Glia 45:170–179

    PubMed  Google Scholar 

  132. Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman E, Mizuno Y (1996) Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci USA 93:2696–2701

    PubMed  CAS  Google Scholar 

  133. Zhang J, Stanton D, Nguyen X, Liu M, Zhang Z, Gash D, Bing G (2005) Intrapallidal lipopolysaccharide injection increases iron and ferritin levels in glia of the rat substantia nigra and induces locomotor deficits. Neuroscience 135:829–838

    PubMed  CAS  Google Scholar 

  134. Zhu J-H, Guo F, Shelburne J, Watkins S, Chu C (2003) Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Brain Pathol 13:473–481

    Article  PubMed  CAS  Google Scholar 

  135. Zhu J-H, Kulich S, Oury T, Chu C (2002) Cytoplasmic aggregates of phosphorylated extracellular signal-regulated kinase in Lewy body diseases. Am J Pathol 161:2087–2098

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Isaac G. Onyango.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Onyango, I.G. Mitochondrial Dysfunction and Oxidative Stress in Parkinson’s Disease. Neurochem Res 33, 589–597 (2008). https://doi.org/10.1007/s11064-007-9482-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-007-9482-y

Keywords

Navigation