title: Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription.
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.
authors.affiliation: Del E. Web Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Ryan
authors.forename: Nima
authors.initials: N
authors.lastname: Dolatabadi
authors.forename: Shing Fai
authors.initials: SF
authors.lastname: Chan
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.forename: Mohd Waseem
authors.initials: MW
authors.lastname: Akhtar
authors.forename: James
authors.initials: J
authors.lastname: Parker
authors.forename: Frank
authors.initials: F
authors.lastname: Soldner
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Sunico
authors.forename: Saumya
authors.initials: S
authors.lastname: Nagar
authors.forename: Maria
authors.initials: M
authors.lastname: Talantova
authors.forename: Brian
authors.initials: B
authors.lastname: Lee
authors.forename: Kevin
authors.initials: K
authors.lastname: Lopez
authors.forename: Anthony
authors.initials: A
authors.lastname: Nutter
authors.forename: Bing
authors.initials: B
authors.lastname: Shan
authors.forename: Elena
authors.initials: E
authors.lastname: Molokanova
authors.forename: Yaoyang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xuemei
authors.initials: X
authors.lastname: Han
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nakanishi
authors.forename: Aleksander Y
authors.initials: AY
authors.lastname: Andreyev
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Okamoto
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ambasudhan
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D059647:Gene-Environment Interaction; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D064326:MEF2 Transcription Factors; D008928:Mitochondria / Q000187:drug effects*; D009154:Mutation / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D010269:Paraquat / Q000633:toxicity*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D026361:Reactive Nitrogen Species / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D026361:Reactive Nitrogen Species; D014157:Transcription Factors; D051844:alpha-Synuclein; D010269:Paraquat