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Molecular Brain
Published in: Molecular Brain 1/2012

Open Access 01-12-2012 | Research

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

Authors: 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 Hayashi, Masanobu Shouji, Atsushi Nakanishi, Norihiro Suzuki, Yoshikuni Mizuno, Noboru Mizushima, Masayuki Amagai, Yasuo Uchiyama, Hideki Mochizuki, Nobutaka Hattori, Hideyuki Okano

Published in: Molecular Brain | Issue 1/2012

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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.
Appendix
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Metadata
Title
Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue
Authors
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 Hayashi
Masanobu Shouji
Atsushi Nakanishi
Norihiro Suzuki
Yoshikuni Mizuno
Noboru Mizushima
Masayuki Amagai
Yasuo Uchiyama
Hideki Mochizuki
Nobutaka Hattori
Hideyuki Okano
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Molecular Brain / Issue 1/2012
Electronic ISSN: 1756-6606
DOI
https://doi.org/10.1186/1756-6606-5-35

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