Parkinson's disease genetic mutations increase cell susceptibility to stress: mutant alpha-synuclein enhances H2O2- and Sin-1-induced cell death.
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 alpha-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.
Jiang
Haibing
H
Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Wu
Yen-Ching
YC
Nakamura
Masayuki
M
Liang
Yideng
Y
Tanaka
Yuji
Y
Holmes
Susan
S
Dawson
Valina L
VL
Dawson
Ted M
TM
Ross
Christopher A
CA
Smith
Wanli W
WW
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D006861:Hydrogen Peroxide / Q000633:toxicity*; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000633:toxicity; D009154:Mutation; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology
D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; C002385:linsidomine; D006861:Hydrogen Peroxide; D008981:Molsidomine