title: Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue.
abstract: BACKGROUND
  Parkinson's disease (PD) is a neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra (SN). The familial form of PD, PARK2, is caused by mutations in the parkin gene. parkin-knockout mouse models show some abnormalities, but they do not fully recapitulate the pathophysiology of human PARK2.
  
  
  RESULTS
  Here, we generated induced pluripotent stem cells (iPSCs) from two PARK2 patients. PARK2 iPSC-derived neurons showed increased oxidative stress and enhanced activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. iPSC-derived neurons, but not fibroblasts or iPSCs, exhibited abnormal mitochondrial morphology and impaired mitochondrial homeostasis. Although PARK2 patients rarely exhibit Lewy body (LB) formation with an accumulation of α-synuclein, α-synuclein accumulation was observed in the postmortem brain of one of the donor patients. This accumulation was also seen in the iPSC-derived neurons in the same patient.
  
  
  CONCLUSIONS
  Thus, pathogenic changes in the brain of a PARK2 patient were recapitulated using iPSC technology. These novel findings reveal mechanistic insights into the onset of PARK2 and identify novel targets for drug screening and potential modified therapies for PD.
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Imaizumi
authors.forename: Yohei
authors.initials: Y
authors.lastname: Okada
authors.forename: Wado
authors.initials: W
authors.lastname: Akamatsu
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.forename: Naoko
authors.initials: N
authors.lastname: Kuzumaki
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayakawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nihira
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Manabu
authors.initials: M
authors.lastname: Ohyama
authors.forename: Shigeto
authors.initials: S
authors.lastname: Sato
authors.forename: Masashi
authors.initials: M
authors.lastname: Takanashi
authors.forename: Manabu
authors.initials: M
authors.lastname: Funayama
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Hirayama
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.forename: Takako
authors.initials: T
authors.lastname: Hishiki
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Takuya
authors.initials: T
authors.lastname: Yagi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.forename: Arifumi
authors.initials: A
authors.lastname: Kosakai
authors.forename: Kozo
authors.initials: K
authors.lastname: Hayashi
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shouji
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakanishi
authors.forename: Norihiro
authors.initials: N
authors.lastname: Suzuki
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amagai
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D063269:Mitochondrial Turnover / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D011180:Postmortem Changes; D015398:Signal Transduction / Q000187:drug effects; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051844:alpha-Synuclein; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone