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

202 Citations (Scopus)

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

Fingerprint

Transcription
Parkinson Disease
Dopaminergic Neurons
Neurons
Maneb
Synucleins
MEF2 Transcription Factors
Rotenone
Paraquat
Oxidative stress
Gene Regulatory Networks
Redox reactions
Cell death
Stem cells
Pesticides
Oxidation-Reduction
Screening
Oxidative Stress
Cell Death
Stem Cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ambasudhan, R., Ryan, S. D., Dolatabadi, N., Chan, S. F., Zhang, X., Akhtar, M. W., ... 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

Isogenic Human iPSC Parkinson’s Model Shows Nitrosative Stress-Induced Dysfunction in MEF2-PGC1α Transcription. / Ambasudhan, Rajesh; Ryan, Scott D.; Dolatabadi, Nima; Chan, Shing Fai; Zhang, Xiaofei; Akhtar, Mohd Waseem; Parker, James; Soldner, Frank; Sunico, Carmen R.; Nagar, Saumya; Talantova, Maria; Lee, Brian; Lopez, Kevin; Nutter, Anthony; Shan, Bing; Molokanova, Elena; Zhang, Yaoyang; Han, Xuemei; Nakamura, Tomohiro; Masliah, Eliezer; Yates, John R.; Nakanishi, Nobuki; Andreyev, Aleksander Y.; Okamoto, Shu Ichi; Jaenisch, Rudolf; Lipton, Stuart A.

In: Cell, Vol. 155, No. 6, 05.12.2013.

Research output: Contribution to journalArticle

Ambasudhan, R, Ryan, SD, Dolatabadi, N, Chan, SF, Zhang, X, Akhtar, MW, Parker, J, Soldner, F, Sunico, CR, Nagar, S, Talantova, M, Lee, B, Lopez, K, Nutter, A, Shan, B, Molokanova, E, Zhang, Y, Han, X, Nakamura, T, Masliah, E, Yates, JR, Nakanishi, N, Andreyev, AY, Okamoto, SI, Jaenisch, R & Lipton, SA 2013, ' Isogenic Human iPSC Parkinson’s Model Shows Nitrosative Stress-Induced Dysfunction in MEF2-PGC1α Transcription', Cell, vol. 155, no. 6. https://doi.org/10.1016/j.cell.2013.11.009
Ambasudhan, Rajesh ; Ryan, Scott D. ; Dolatabadi, Nima ; Chan, Shing Fai ; Zhang, Xiaofei ; Akhtar, Mohd Waseem ; Parker, James ; Soldner, Frank ; Sunico, Carmen R. ; Nagar, Saumya ; Talantova, Maria ; Lee, Brian ; Lopez, Kevin ; Nutter, Anthony ; Shan, Bing ; Molokanova, Elena ; Zhang, Yaoyang ; Han, Xuemei ; Nakamura, Tomohiro ; Masliah, Eliezer ; Yates, John R. ; Nakanishi, Nobuki ; Andreyev, Aleksander Y. ; Okamoto, Shu Ichi ; Jaenisch, Rudolf ; Lipton, Stuart A. / Isogenic Human iPSC Parkinson’s Model Shows Nitrosative Stress-Induced Dysfunction in MEF2-PGC1α Transcription. In: Cell. 2013 ; Vol. 155, No. 6.
@article{9e87407cd5274551b6591ff26a46fbb5,
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.",
author = "Rajesh Ambasudhan and Ryan, {Scott D.} and Nima Dolatabadi and Chan, {Shing Fai} and Xiaofei Zhang and Akhtar, {Mohd Waseem} and James Parker and Frank Soldner and Sunico, {Carmen R.} and Saumya Nagar and Maria Talantova and Brian Lee and Kevin Lopez and Anthony Nutter and Bing Shan and Elena Molokanova and Yaoyang Zhang and Xuemei Han and Tomohiro Nakamura and Eliezer Masliah and Yates, {John R.} and Nobuki Nakanishi and Andreyev, {Aleksander Y.} and Okamoto, {Shu Ichi} and Rudolf Jaenisch and Lipton, {Stuart A.}",
year = "2013",
month = "12",
day = "5",
doi = "10.1016/j.cell.2013.11.009",
language = "English (US)",
volume = "155",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - Isogenic Human iPSC Parkinson’s Model Shows Nitrosative Stress-Induced Dysfunction in MEF2-PGC1α Transcription

AU - Ambasudhan, Rajesh

AU - Ryan, Scott D.

AU - Dolatabadi, Nima

AU - Chan, Shing Fai

AU - Zhang, Xiaofei

AU - Akhtar, Mohd Waseem

AU - Parker, James

AU - Soldner, Frank

AU - Sunico, Carmen R.

AU - Nagar, Saumya

AU - Talantova, Maria

AU - Lee, Brian

AU - Lopez, Kevin

AU - Nutter, Anthony

AU - Shan, Bing

AU - Molokanova, Elena

AU - Zhang, Yaoyang

AU - Han, Xuemei

AU - Nakamura, Tomohiro

AU - Masliah, Eliezer

AU - Yates, John R.

AU - Nakanishi, Nobuki

AU - Andreyev, Aleksander Y.

AU - Okamoto, Shu Ichi

AU - Jaenisch, Rudolf

AU - Lipton, Stuart A.

PY - 2013/12/5

Y1 - 2013/12/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84890115517&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890115517&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2013.11.009

DO - 10.1016/j.cell.2013.11.009

M3 - Article

C2 - 24290359

AN - SCOPUS:84890115517

VL - 155

JO - Cell

JF - Cell

SN - 0092-8674

IS - 6

ER -