NADPH Oxidase 1-mediated Oxidative Stress Leads to Dopamine Neuron Death in Parkinson's Disease

Antioxid Redox Signal. 2012 May 15;16(10):1033-45. doi: 10.1089/ars.2011.3960. Epub 2012 Jan 25.

Abstract

Aim: 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.

Innovation: Nox1/Rac1 could serve as a potential therapeutic target for Parkinson's disease.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cell Line
  • Cell Nucleus / metabolism
  • Corpus Striatum / metabolism
  • DNA Damage
  • Dopaminergic Neurons / enzymology*
  • Dopaminergic Neurons / pathology*
  • Gene Expression
  • Gene Silencing
  • Humans
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors
  • NADH, NADPH Oxidoreductases / genetics
  • NADH, NADPH Oxidoreductases / metabolism*
  • NADPH Oxidase 1
  • Oxidative Stress*
  • Oxidopamine / pharmacology
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology*
  • Protein Transport
  • Rats
  • Reactive Oxygen Species / metabolism
  • rac1 GTP-Binding Protein / antagonists & inhibitors
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Reactive Oxygen Species
  • Oxidopamine
  • NADH, NADPH Oxidoreductases
  • NADPH Oxidase 1
  • NOX1 protein, rat
  • rac1 GTP-Binding Protein