Isogenic Human iPSC Parkinson’s Model Shows Nitrosative Stress-Induced Dysfunction in MEF2-PGC1α Transcription

Rajesh Ambasudhan, Scott D. Ryan, Nima Dolatabadi, Shing Fai Chan, Xiaofei Zhang, Mohd Waseem Akhtar, James Parker, Frank Soldner, Carmen R. Sunico, Saumya Nagar, Maria Talantova, Brian Lee, Kevin Lopez, Anthony Nutter, Bing Shan, Elena Molokanova, Yaoyang Zhang, Xuemei Han, Tomohiro Nakamura, Eliezer MasliahJohn R. Yates, Nobuki Nakanishi, Aleksander Y. Andreyev, Shu Ichi Okamoto, Rudolf Jaenisch, Stuart A. Lipton

Research output: Contribution to journalArticle

220 Scopus citations

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.

Original languageEnglish (US)
Number of pages1
JournalCell
Volume155
Issue number6
DOIs
StatePublished - Dec 5 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ambasudhan, R., Ryan, S. D., Dolatabadi, N., Chan, S. F., Zhang, X., Akhtar, M. W., Parker, J., Soldner, F., Sunico, C. R., Nagar, S., Talantova, M., Lee, B., Lopez, K., Nutter, A., Shan, B., Molokanova, E., Zhang, Y., Han, X., Nakamura, T., ... Lipton, S. A. (2013). Isogenic Human iPSC Parkinson’s Model Shows Nitrosative Stress-Induced Dysfunction in MEF2-PGC1α Transcription. Cell, 155(6). https://doi.org/10.1016/j.cell.2013.11.009