1. Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson’s Disease
- Author
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Owen A. Ross, Ole Isacson, Maria Sundberg, Joseph R. Mazzulli, Hyemyung Seo, Serge Przedborski, Houbo Jiang, Eduardo Perez-Torres, Li Chen, Leslie A. Scarffe, Lorraine N. Clark, Karen Marder, Grzegorz Opala, Christine Klein, Luis Carrillo-Reid, Jesse R. McLean, Virginia M.-Y. Lee, Oliver Cooper, Laura A. Volpicelli-Daley, Shaida A. Andrabi, Helle Bogetofte, Ryan J. Uitti, Tristan Lawson, Norma Romero, Jian Feng, Gunnar Hargus, Carol Moskowitz, Valina L. Dawson, Michela Deleidi, Dimitri Krainc, Cristina Guardia-Laguarta, Zhigao Huang, John J. Graziotto, Ted M. Dawson, D. James Surmeier, Zhong Xie, John Q. Trojanowski, Zbigniew K. Wszolek, and Teresia Osborn
- Subjects
Coenzyme Q10 ,Genetics ,Parkinson's disease ,Kinase ,PINK1 ,General Medicine ,Mitochondrion ,Biology ,medicine.disease ,medicine.disease_cause ,LRRK2 ,chemistry.chemical_compound ,chemistry ,Cancer research ,medicine ,Induced pluripotent stem cell ,Oxidative stress - Abstract
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 )a ndLRRK2 (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 Q10, rapamycin, or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSCderived 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.
- Published
- 2012