Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue

Yoichi Imaizumi, Yohei Okada, Wado Akamatsu, Masato Koike, Naoko Kuzumaki, Hideki Hayakawa, Tomoko Nihira, Tetsuro Kobayashi, Manabu Ohyama, Shigeto Sato, Masashi Takanashi, Manabu Funayama, Akiyoshi Hirayama, Tomoyoshi Soga, Takako Hishiki, Makoto Suematsu, Takuya Yagi, Daisuke Ito, Arifumi Kosakai, Kozo HayashiMasanobu Shouji, Atsushi Nakanishi, Norihiro Suzuki, Yoshikuni Mizuno, Noboru Mizushima, Masayuki Amagai, Yasuo Uchiyama, Hideki Mochizuki, Nobutaka Hattori, Hideyuki Okano

Research output: Contribution to journalArticle

215 Citations (Scopus)

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.

Original languageEnglish
Article number35
JournalMolecular brain
Volume5
Issue number1
DOIs
Publication statusPublished - 2012 Oct 9

Keywords

  • Induced pluripotent stem cells
  • Mitochondria
  • Oxidative stress
  • Parkin
  • Parkinson's disease
  • α-synuclein

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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    Imaizumi, Y., Okada, Y., Akamatsu, W., Koike, M., Kuzumaki, N., Hayakawa, H., Nihira, T., Kobayashi, T., Ohyama, M., Sato, S., Takanashi, M., Funayama, M., Hirayama, A., Soga, T., Hishiki, T., Suematsu, M., Yagi, T., Ito, D., Kosakai, A., ... Okano, H. (2012). Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue. Molecular brain, 5(1), [35]. https://doi.org/10.1186/1756-6606-5-35