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

Yoichi Imaizumi1, Yohei Okada12, Wado Akamatsu1, Masato Koike3, Naoko Kuzumaki1, Hideki Hayakawa4, Tomoko Nihira4, Tetsuro Kobayashi5, Manabu Ohyama5, Shigeto Sato6, Masashi Takanashi6, Manabu Funayama67, Akiyoshi Hirayama8, Tomoyoshi Soga8, Takako Hishiki9, Makoto Suematsu9, Takuya Yagi10, Daisuke Ito10, Arifumi Kosakai10, Kozo Hayashi11, Masanobu Shouji11, Atsushi Nakanishi11, Norihiro Suzuki10, Yoshikuni Mizuno12, Noboru Mizushima13, Masayuki Amagai5, Yasuo Uchiyama3, Hideki Mochizuki144, Nobutaka Hattori67 and Hideyuki Okano1*

Author Affiliations

1 Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

2 Kanrinmaru Project, Keio University School of Medicine, Tokyo, Japan

3 Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan

4 Department of Neurology, Kitasato University School of Medicine, Kanagawa, Japan

5 Department of Dermatology, Keio University School of Medicine, Tokyo, Japan

6 Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan

7 Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo, Japan

8 Institute for Advanced Biosciences, Keio University, Yamagata, Japan

9 Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan

10 Department of Neurology, Keio University School of Medicine, Tokyo, Japan

11 Advanced Science Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan

12 Department of Neuro-Regenerative Medicine, Kitasato University School of Medicine, Kanagawa, Japan

13 Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan

14 Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan

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Molecular Brain 2012, 5:35  doi:10.1186/1756-6606-5-35

Published: 6 October 2012

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.

Keywords:
Induced pluripotent stem cells; Parkinson’s disease; Parkin; Oxidative stress; Mitochondria; α-synuclein