期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 45, 期 3, 页码 242-255出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2008.03.022
关键词
aggresome; dopamine; glutathione; heat shock protein; methionine sulfaxide reductase; neurodegeneration; oxidative stress; Parkinson's disease; proteasome; protofibril; rotenone; synuclein
资金
- NCI NIH HHS [P30 CA023168] Funding Source: Medline
- NIA NIH HHS [R03 AG027123-01, R03 AG027123, R03 AG027123-02] Funding Source: Medline
- NIGMS NIH HHS [R01 GM067195] Funding Source: Medline
- NINDS NIH HHS [R01 NS049221-02, R01 NS049221-01A2, R01 NS049221-03, R01 NS049221] Funding Source: Medline
Parkinson's disease (PD) is a neurologic disorder characterized by dopaminergic cell death in the substantia nigra. PD pathogenesis involves mitochondrial dysfunction, proteasome impairment, and a-synuclein aggregation, insults that may be especially toxic to oxidatively stressed cells including dopaminergic neurons. The enzyme methionine sulfoxide reductase A (MsrA) plays a critical role in the antioxidant response by repairing methionine-oxidized proteins and by participating in cycles of methionine oxidation and reduction that have the net effect of consuming reactive oxygen species. Here, we show that MsrA suppresses dopaminergic cell death and protein aggregation induced by the complex I inhibitor rotenone or mutant alpha-synuclein, but not by the proteasome inhibitor MG132. By comparing the effects of MsrA and the small-molecule antioxidants N-acetylcysteine and vitamin E, we provide evidence that MsrA protects against PD-related stresses primarily via methionine sulfoxide repair rather than by scavenging reactive oxygen species. We also demonstrate that MsrA efficiently reduces oxidized methionine residues in recombinant alpha-synuclein. These findings suggest that enhancing MsrA function may be a reasonable therapeutic strategy in PD. (c) 2008 Elsevier Inc. All rights reserved.
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