TY - JOUR
T1 - Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease
AU - Cooper, Oliver
AU - Seo, Hyemyung
AU - Andrabi, Shaida
AU - Guardia-Laguarta, Cristina
AU - Graziotto, John
AU - Sundberg, Maria
AU - McLean, Jesse R.
AU - Carrillo-Reid, Luis
AU - Xie, Zhong
AU - Osborn, Teresia
AU - Hargus, Gunnar
AU - Deleidi, Michela
AU - Lawson, Tristan
AU - Bogetofte, Helle
AU - Perez-Torres, Eduardo
AU - Clark, Lorraine
AU - Moskowitz, Carol
AU - Mazzulli, Joseph
AU - Chen, Li
AU - Volpicelli-Daley, Laura
AU - Romero, Norma
AU - Jiang, Houbo
AU - Uitti, Ryan J.
AU - Huang, Zhigao
AU - Opala, Grzegorz
AU - Scarffe, Leslie A.
AU - Dawson, Valina L.
AU - Klein, Christine
AU - Feng, Jian
AU - Ross, Owen A.
AU - Trojanowski, John Q.
AU - Lee, Virginia M.Y.
AU - Marder, Karen
AU - Surmeier, D. James
AU - Wszolek, Zbigniew K.
AU - Przedborski, Serge
AU - Krainc, Dimitri
AU - Dawson, Ted M.
AU - Isacson, Ole
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/7/4
Y1 - 2012/7/4
N2 - Parkinson's disease (PD) is a common neurodegenerative disorder caused by genetic and environmental factors that results in degeneration of the nigrostriatal dopaminergic pathway in the brain. We analyzed neural cells generated from induced pluripotent stem cells (iPSCs) derived from PD patients and presymptomatic individuals carrying mutations in the PINK1 (PTEN-induced putative kinase 1) and LRRK2 (leucine-rich repeat kinase 2) genes, and compared them to those of healthy control subjects. We measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage, and intraneuronal movement of mitochondria. Cellular vulnerability associated with mitochondrial dysfunction in iPSC-derived neural cells from familial PD patients and at-risk individuals could be rescued with coenzyme Q 10, rapamycin, or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSC-derived neural cells from PD patients carrying different mutations provides insight into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in this neurodegenerative disease.
AB - Parkinson's disease (PD) is a common neurodegenerative disorder caused by genetic and environmental factors that results in degeneration of the nigrostriatal dopaminergic pathway in the brain. We analyzed neural cells generated from induced pluripotent stem cells (iPSCs) derived from PD patients and presymptomatic individuals carrying mutations in the PINK1 (PTEN-induced putative kinase 1) and LRRK2 (leucine-rich repeat kinase 2) genes, and compared them to those of healthy control subjects. We measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage, and intraneuronal movement of mitochondria. Cellular vulnerability associated with mitochondrial dysfunction in iPSC-derived neural cells from familial PD patients and at-risk individuals could be rescued with coenzyme Q 10, rapamycin, or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSC-derived neural cells from PD patients carrying different mutations provides insight into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in this neurodegenerative disease.
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U2 - 10.1126/scitranslmed.3003985
DO - 10.1126/scitranslmed.3003985
M3 - Article
C2 - 22764206
AN - SCOPUS:84863584524
VL - 4
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 141
M1 - 141ra90
ER -