Journal
NEUROBIOLOGY OF AGING
Volume 28, Issue 11, Pages 1709-1717Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2006.07.017
Keywords
Parkinson's disease; alpha-synuclein; cell death; oxidative stress; nitrative stress; Sin-1; ROS; 3-nitrotyrosine
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Funding
- NINDS NIH HHS [NS38377] Funding Source: Medline
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Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. alpha-Synuclein is a major component of Lewy bodies in sporadic PD, and genetic alterations in alpha-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 a-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 alpha-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 alpha-synuclein, and further increased after Sin-1 (a NO donor) treatment compared with untreated or treated non-induced cells. Expression of alpha-synuclein (mutant more than wild type) significantly enhances Sin-1 toxicity. These results indicate that genetic mutations in alpha-synuclein may increase neuronal vulnerability to cellular stress in aging and PD pathogenesis. (c) 2006 Elsevier Inc. All rights reserved.
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