Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson's Disease

被引：350

作者：

Cooper, Oliver ^{[1
]}

Seo, Hyemyung ^{[1
]}

Andrabi, Shaida ^{[2
,3
,4
,5
]}

Guardia-Laguarta, Cristina ^{[6
,7
,8
,9
]}

Graziotto, John ^{[10
]}

Sundberg, Maria ^{[1
]}

McLean, Jesse R. ^{[1
]}

Carrillo-Reid, Luis ^{[11
]}

Xie, Zhong ^{[11
]}

Osborn, Teresia ^{[1
]}

Hargus, Gunnar ^{[1
]}

Deleidi, Michela ^{[1
]}

Lawson, Tristan ^{[1
]}

Bogetofte, Helle ^{[1
]}

Perez-Torres, Eduardo ^{[1
]}

Clark, Lorraine ^{[6
,7
,8
,9
]}

Moskowitz, Carol ^{[6
,7
,8
,9
]}

Mazzulli, Joseph ^{[10
]}

Chen, Li ^{[2
,3
,4
,5
]}

Volpicelli-Daley, Laura ^{[12
,13
]}

Romero, Norma ^{[6
,7
,8
,9
]}

Jiang, Houbo ^{[14
]}

Uitti, Ryan J. ^{[15
,16
]}

Huang, Zhigao ^{[17
]}

Opala, Grzegorz ^{[18
]}

Scarffe, Leslie A. ^{[2
,3
,4
,5
]}

Dawson, Valina L. ^{[2
,3
,4
,5
]}

Klein, Christine ^{[19
]}

Feng, Jian ^{[14
]}

Ross, Owen A. ^{[15
,16
]}

Trojanowski, John Q. ^{[12
,13
]}

Lee, Virginia M. -Y. ^{[12
,13
]}

Marder, Karen ^{[6
,7
,8
,9
]}

Surmeier, D. James ^{[11
]}

Wszolek, Zbigniew K. ^{[15
,16
]}

Przedborski, Serge ^{[6
,7
,8
,9
]}

Krainc, Dimitri ^{[10
]}

Dawson, Ted M. ^{[2
,3
,4
,5
]}

Isacson, Ole ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, McLean Hosp, Neuroregenerat Inst, Belmont, MA 02478 USA

[2] Johns Hopkins Univ, Sch Med, Neuroregenerat Program, Inst Cell Engn, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Stem Cell Program, Inst Cell Engn, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[6] Columbia Univ, Sergievsky Ctr, Taub Inst, Dept Neurol, New York, NY 10032 USA

[7] Columbia Univ, Sergievsky Ctr, Taub Inst, Dept Psychiat, New York, NY 10032 USA

[8] Columbia Univ, Sergievsky Ctr, Taub Inst, Dept Pathol & Cell Biol, New York, NY 10032 USA

[9] Columbia Univ, Ctr Motor Neuron Biol & Dis, New York, NY 10032 USA

[10] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA

[11] Northwestern Univ, Feinberg Sch Med, Dept Physiol, Chicago, IL 60611 USA

[12] Univ Penn, Sch Med, Dept Pathol & Lab Med, Inst Aging, Philadelphia, PA 19104 USA

[13] Univ Penn, Sch Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA

[14] SUNY Buffalo, Dept Physiol & Biophys, Buffalo, NY 14214 USA

[15] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

[16] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[17] Univ Florida Shands, Jacksonville, FL 32209 USA

[18] Med Univ Silesia, Dept Neurol, PL-40055 Katowice, Poland

[19] Med Univ Lubeck, Sect Clin & Mol Neurogenet, Dept Neurol, D-23562 Lubeck, Germany

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2012年 / 4卷 / 141期

关键词：

PLURIPOTENT STEM-CELLS; AUTOSOMAL-DOMINANT PARKINSONISM; EARLY-ONSET PARKINSONISM; DOPAMINERGIC-NEURONS; SUBSTANTIA-NIGRA; AXONAL-TRANSPORT; CLINICAL-FEATURES; GENETIC-ANALYSIS; PINK1; MUTATIONS; BAFILOMYCIN A1;

D O I：

10.1126/scitranslmed.3003985

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：13

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