Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease

Oliver Cooper, Hyemyung Seo, Shaida Andrabi, Cristina Guardia-Laguarta, John Graziotto, Maria Sundberg, Jesse R. McLean, Luis Carrillo-Reid, Zhong Xie, Teresia Osborn, Gunnar Hargus, Michela Deleidi, Tristan Lawson, Helle Bogetofte, Eduardo Perez-Torres, Lorraine Clark, Carol Moskowitz, Joseph Mazzulli, Li Chen, Laura Volpicelli-DaleyNorma Romero, Houbo Jiang, Ryan J. Uitti, Zhigao Huang, Grzegorz Opala, Leslie A. Scarffe, Valina L. Dawson, Christine Klein, Jian Feng, Owen A Ross, John Q. Trojanowski, Virginia M Y Lee, Karen Marder, D. James Surmeier, Zbigniew K Wszolek, Serge Przedborski, Dimitri Krainc, Ted M. Dawson, Ole Isacson

Research output: Contribution to journalArticle

277 Citations (Scopus)

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) 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.

Original languageEnglish (US)
Article number141ra90
JournalScience Translational Medicine
Volume4
Issue number141
DOIs
StatePublished - Jul 4 2012

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Induced Pluripotent Stem Cells
Parkinson Disease
Pharmacology
Phosphotransferases
Leucine
Neurodegenerative Diseases
Mutation
Ubiquinone
Sirolimus
Protons
Reactive Oxygen Species
Healthy Volunteers
Mitochondria
Respiration
Oxidative Stress
Brain
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease. / 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.

In: Science Translational Medicine, Vol. 4, No. 141, 141ra90, 04.07.2012.

Research output: Contribution to journalArticle

Cooper, O, Seo, H, Andrabi, S, Guardia-Laguarta, C, Graziotto, J, Sundberg, M, McLean, JR, Carrillo-Reid, L, Xie, Z, Osborn, T, Hargus, G, Deleidi, M, Lawson, T, Bogetofte, H, Perez-Torres, E, Clark, L, Moskowitz, C, Mazzulli, J, Chen, L, Volpicelli-Daley, L, Romero, N, Jiang, H, Uitti, RJ, Huang, Z, Opala, G, Scarffe, LA, Dawson, VL, Klein, C, Feng, J, Ross, OA, Trojanowski, JQ, Lee, VMY, Marder, K, Surmeier, DJ, Wszolek, ZK, Przedborski, S, Krainc, D, Dawson, TM & Isacson, O 2012, 'Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease', Science Translational Medicine, vol. 4, no. 141, 141ra90. https://doi.org/10.1126/scitranslmed.3003985
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. / Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease. In: Science Translational Medicine. 2012 ; Vol. 4, No. 141.
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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) 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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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

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.

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