Isogenic Human iPSC Parkinson’s Model Shows Nitrosative Stress-Induced Dysfunction in MEF2-PGC1α Transcription
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Author(s)
Ryan, Scott D.
Dolatabadi, Nima
Chan, Shing Fai
Zhang, Xiaofei
Akhtar, Mohd Waseem
Parker, James
Soldner, Frank
Sunico, Carmen R.
Nagar, Saumya
Talantova, Maria
Date Issued
December 2013
Journal
Cell
Publisher
Elsevier
Citation
Ryan, Scott D., Nima Dolatabadi, Shing Fai Chan, Xiaofei Zhang, Mohd Waseem Akhtar, James Parker, Frank Soldner, et al. "Isogenic Human iPSC Parkinson’s Model Shows Nitrosative Stress-Induced Dysfunction in MEF2-PGC1α Transcription." Cell 155:6 (December 2015), pp.1351-1364.
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Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1016/j.cell.2013.11.009
