Familial Parkinson's disease iPSCs show cellular deficits in mitochondrial responses that can be pharmacologically rescued

Parkinson's disease (PD) is a common neurodegenerative disease caused by genetic and environmental factors. We analyzed induced pluripotent stem cell (iPSC)-derived neural cells from PD patients and presymptomatic individuals carrying mutations in the PINK1 and LRRK2 genes, and healthy control...

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Published in:Science translational medicine 2012-07, Vol.4 (141), p.141ra90-141ra90
Main Authors: Cooper, Oliver, Seo, Hyemyung, Andrabi, Shaida, Guardia-Laguarta, Cristina, Graziotto, John, Sundberg, Maria, McLean, Jesse R., Carrillo-Reid, Luis, Xie, Zhong, Osborn, Teresia, Hargus, Gunnar, Deleidi, Michela, Lawson, Tristan, Bogetofte, Helle, Perez-Torres, Eduardo, Clark, Lorraine, Moskowitz, Carol, Mazzulli, Joseph, Chen, Li, Volpicelli-Daley, Laura, Romero, Norma, Jiang, Houbo, Uitti, Ryan J., Huang, Zhigao, Opala, Grzegorz, Scarffe, Leslie A., Dawson, Valina L., Klein, Christine, Feng, Jian, Ross, Owen A., Trojanowski, John Q., Lee, Virginia M.-Y., Marder, Karen, Surmeier, D. James, Wszolek, Zbigniew K., Przedborski, Serge, Krainc, Dimitri, Dawson, Ted M., Isacson, Ole
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Language:English
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Summary:Parkinson's disease (PD) is a common neurodegenerative disease caused by genetic and environmental factors. We analyzed induced pluripotent stem cell (iPSC)-derived neural cells from PD patients and presymptomatic individuals carrying mutations in the PINK1 and LRRK2 genes, and 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 function in iPSC-derived neural cells from 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 insights into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in PD.
ISSN:1946-6234
1946-6242
DOI:10.1126/scitranslmed.3003985