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 Masliah; John R. Yates; Nobuki Nakanishi; Aleksander Y. Andreyev; Shu Ichi Okamoto; Rudolf Jaenisch; Stuart A. Lipton

doi:10.1016/j.cell.2013.11.009

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

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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 language	English (US)
Pages (from-to)	1351
Number of pages	1
Journal	Cell
Volume	155
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2013.11.009
State	Published - Dec 5 2013
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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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), 1351. https://doi.org/10.1016/j.cell.2013.11.009

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, pp. 1351. https://doi.org/10.1016/j.cell.2013.11.009

@article{9e87407cd5274551b6591ff26a46fbb5,

title = " Isogenic Human iPSC Parkinson{\textquoteright}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.}",

note = "Funding Information: This work was supported in part by NIH grants P01 HD29587, P01 ES016738, and P30 NS076411 (to S.A.L.); R37 CA084198 (to R.J.); United Mitochondrial Disease Foundation grant (to R.A.); and a Parkinson Society of Canada Fellowship (to S.D.R.). ",

year = "2013",

month = dec,

day = "5",

doi = "10.1016/j.cell.2013.11.009",

language = "English (US)",

volume = "155",

pages = "1351",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "6",

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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.

N1 - Funding Information: This work was supported in part by NIH grants P01 HD29587, P01 ES016738, and P30 NS076411 (to S.A.L.); R37 CA084198 (to R.J.); United Mitochondrial Disease Foundation grant (to R.A.); and a Parkinson Society of Canada Fellowship (to S.D.R.).

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.

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U2 - 10.1016/j.cell.2013.11.009

DO - 10.1016/j.cell.2013.11.009

M3 - Article

C2 - 24290359

AN - SCOPUS:84890115517

SN - 0092-8674

VL - 155

SP - 1351

JO - Cell

JF - Cell

IS - 6

ER -

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

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