title: Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease.
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.
authors: Neuroregeneration Institute, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
authors: Oliver
authors: O
authors: Cooper
authors: Hyemyung
authors: H
authors: Seo
authors: Shaida
authors: S
authors: Andrabi
authors: Cristina
authors: C
authors: Guardia-Laguarta
authors: John
authors: J
authors: Graziotto
authors: Maria
authors: M
authors: Sundberg
authors: Jesse R
authors: JR
authors: McLean
authors: Luis
authors: L
authors: Carrillo-Reid
authors: Zhong
authors: Z
authors: Xie
authors: Teresia
authors: T
authors: Osborn
authors: Gunnar
authors: G
authors: Hargus
authors: Michela
authors: M
authors: Deleidi
authors: Tristan
authors: T
authors: Lawson
authors: Helle
authors: H
authors: Bogetofte
authors: Eduardo
authors: E
authors: Perez-Torres
authors: Lorraine
authors: L
authors: Clark
authors: Carol
authors: C
authors: Moskowitz
authors: Joseph
authors: J
authors: Mazzulli
authors: Li
authors: L
authors: Chen
authors: Laura
authors: L
authors: Volpicelli-Daley
authors: Norma
authors: N
authors: Romero
authors: Houbo
authors: H
authors: Jiang
authors: Ryan J
authors: RJ
authors: Uitti
authors: Zhigao
authors: Z
authors: Huang
authors: Grzegorz
authors: G
authors: Opala
authors: Leslie A
authors: LA
authors: Scarffe
authors: Valina L
authors: VL
authors: Dawson
authors: Christine
authors: C
authors: Klein
authors: Jian
authors: J
authors: Feng
authors: Owen A
authors: OA
authors: Ross
authors: John Q
authors: JQ
authors: Trojanowski
authors: Virginia M-Y
authors: VM
authors: Lee
authors: Karen
authors: K
authors: Marder
authors: D James
authors: DJ
authors: Surmeier
authors: Zbigniew K
authors: ZK
authors: Wszolek
authors: Serge
authors: S
authors: Przedborski
authors: Dimitri
authors: D
authors: Krainc
authors: Ted M
authors: TM
authors: Dawson
authors: Ole
authors: O
authors: Isacson
mesh_terms: D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D010636:Phenols / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D020123:Sirolimus / Q000627:therapeutic use; D014451:Ubiquinone / Q000627:therapeutic use
chemical_list: D007211:Indoles; D010636:Phenols; D014451:Ubiquinone; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; C489251:5-iodo-3-((3,5-dibromo-4-hydroxyphenyl)methylene)-2-indolinone; D020123:Sirolimus