title: NADPH oxidase 1-mediated oxidative stress leads to dopamine neuron death in Parkinson's disease.
abstract: OBJECTIVE
  Oxidative stress has long been considered as a major contributing factor in the pathogenesis of Parkinson's disease. However, molecular sources for reactive oxygen species in Parkinson's disease have not been clearly elucidated. Herein, we sought to investigate whether a superoxide-producing NADPH oxidases (NOXs) are implicated in oxidative stress-mediated dopaminergic neuronal degeneration.
  
  
  RESULTS
  Expression of various Nox isoforms and cytoplasmic components were investigated in N27, rat dopaminergic cells. While most of Nox isoforms were constitutively expressed, Nox1 expression was significantly increased after treatment with 6-hydroxydopamine. Rac1, a key regulator in the Nox1 system, was also activated. Striatal injection of 6-hydroxydopamine increased Nox1 expression in dopaminergic neurons in the rat substantia nigra. Interestingly, it was localized into the nucleus, and immunostaining for DNA oxidative stress marker, 8-oxo-dG, was increased. Nox1 expression was also found in the nucleus of dopaminergic neurons in the substantia nigra of Parkinson's disease patients. Adeno-associated virus-mediated Nox1 knockdown or Rac1 inhibition reduced 6-hydroxydopamine-induced oxidative DNA damage and dopaminergic neuronal degeneration significantly.
  
  
  METHODS
  Nox1/Rac1 could serve as a potential therapeutic target for Parkinson's disease.
  
  
  CONCLUSIONS
  We provide evidence that dopaminergic neurons are equipped with the Nox1/Rac1 superoxide-generating system. Stress-induced Nox1/Rac1 activation causes oxidative DNA damage and neurodegeneration. Reduced dopaminergic neuronal death achieved by targeting Nox1/Rac1, emphasizes the impact of oxidative stress caused by this system on the pathogenesis and therapy in Parkinson's disease.
authors.affiliation: Neurology/Neuroscience Department, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Dong-Hee
authors.initials: DH
authors.lastname: Choi
authors.forename: Ana Clara
authors.initials: AC
authors.lastname: Cristóvão
authors.forename: Subhrangshu
authors.initials: S
authors.lastname: Guhathakurta
authors.forename: Jongmin
authors.initials: J
authors.lastname: Lee
authors.forename: Tong H
authors.initials: TH
authors.lastname: Joh
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Yoon-Seong
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004249:DNA Damage; D059290:Dopaminergic Neurons / Q000201:enzymology* / Q000473:pathology*; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D018384:Oxidative Stress; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D021381:Protein Transport; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D016627:Oxidopamine; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614712:NOX1 protein, rat; D020830:rac1 GTP-Binding Protein
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