期刊
CELL
卷 155, 期 6, 页码 1351-1364出版社
CELL PRESS
DOI: 10.1016/j.cell.2013.11.009
关键词
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资金
- NIH [P01 HD29587, P01 ES016738, P30 NS076411]
- United Mitochondrial Disease Foundation
- Parkinson Society of Canada Fellowship
- [R37 CA084198]
Parkinson's disease (PD) is characterized by loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). An association has been reported between PD and exposure to mitochondrial toxins, including environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patient-derived stem cell model of PD allowing comparison of A53T alpha-synuclein (alpha-syn) mutant cells and isogenic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations in A53T alpha-syn A9 DA neurons (hNs). We report a pathway whereby basal and toxin-induced nitrosative/oxidative stress results in S-nitrosylation of transcription factor MEF2C in A53T hNs compared to corrected controls. This redox reaction inhibits the MEF2-CPGC1 alpha transcriptional network, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction (GxE) in the pathogenesis of PD. Furthermore, using small-molecule high-throughput screening, we identify the MEF2C-PGC1 alpha pathway as a therapeutic target to combat PD.
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