Author/Authors :
cott D. Ryan، نويسنده , , Nima Dolatabadi، نويسنده , , Shing Fai Chan، نويسنده , , Xiaofei Zhang، نويسنده , , Mohd Waseem Akhtar، نويسنده , , James Parker، نويسنده , , Frank Soldner، نويسنده , , Carmen R. Sunico، نويسنده , , Saumya Nagar، نويسنده , , Maria Talantova، نويسنده , , Brian Lee، نويسنده , , Kevin Lopez، نويسنده , , Anthony Nutter، نويسنده , , Bing Shan، نويسنده , , Elena Molokanova، نويسنده , , Yaoyang Zhang، نويسنده , , Xuemei Han، نويسنده , , Tomohiro Nakamura، نويسنده , , Eliezer Masliah، نويسنده , , John R. Yates III، نويسنده , , et al.، نويسنده ,
Abstract :
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 α-synuclein (α-syn) mutant cells and isogenic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations in A53T α-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 MEF2C-PGC1α 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-PGC1α pathway as a therapeutic target to combat PD.
