Parkinson's disease genetic mutations increase cell susceptibility to stress: Mutant α-synuclein enhances H2O2- and Sin-1-induced cell death

Haibing Jiang, Yen Ching Wu, Masayuki Nakamura, Yideng Liang, Yuji Tanaka, Susan Holmes, Valina L. Dawson, Ted M. Dawson, Christopher A. Ross, Wanli W. Smith

Research output: Contribution to journalArticle

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. α-Synuclein is a major component of Lewy bodies in sporadic PD, and genetic alterations in α-synuclein cause autosomal-dominant hereditary PD. The pathogenesis of PD remains incompletely understood, but it appears to involve both genetic susceptibility and environmental factors. Here we investigated the effect of α-synuclein expression on cell susceptibility to proteasome inhibition, oxidative and nitrative stresses by using a PC 12-Tet-off regulatory system. We found that inducible expression of A30P or A53T mutant α-synuclein decreased the proteasome activity, increased intracellular ROS levels, and enhanced lactacystin- and H2O2-induced cell death. Furthermore, 3-nitrotyrosine levels increased in cells expressing α-synuclein, and further increased after Sin-1 (a NO donor) treatment compared with untreated or treated non-induced cells. Expression of α-synuclein (mutant more than wild type) significantly enhances Sin-1 toxicity. These results indicate that genetic mutations in α-synuclein may increase neuronal vulnerability to cellular stress in aging and PD pathogenesis.

Original languageEnglish (US)
Pages (from-to)1709-1717
Number of pages9
JournalNeurobiology of Aging
Volume28
Issue number11
DOIs
StatePublished - Nov 1 2007

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Keywords

  • 3-Nitrotyrosine
  • Cell death
  • Nitrative stress
  • Oxidative stress
  • Parkinson's disease
  • ROS
  • Sin-1
  • α-Synuclein

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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