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

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• 作者：Yoichi Imaizumi (1)
  Yohei Okada (1) (2)
  Wado Akamatsu (1)
  Masato Koike (3)
  Naoko Kuzumaki (1)
  Hideki Hayakawa (4)
  Tomoko Nihira (4)
  Tetsuro Kobayashi (5)
  Manabu Ohyama (5)
  Shigeto Sato (6)
  Masashi Takanashi (6)
  Manabu Funayama (6) (7)
  Akiyoshi Hirayama (8)
  Tomoyoshi Soga (8)
  Takako Hishiki (9)
  Makoto Suematsu (9)
  Takuya Yagi (10)
  Daisuke Ito (10)
  Arifumi Kosakai (10)
  Kozo Hayashi (11)
  Masanobu Shouji (11)
  Atsushi Nakanishi (11)
  Norihiro Suzuki (10)
  Yoshikuni Mizuno (12)
  Noboru Mizushima (13)
  Masayuki Amagai (5)
  Yasuo Uchiyama (3)
  Hideki Mochizuki (14) (4)
  Nobutaka Hattori (6) (7)
  Hideyuki Okano (1)
  
• 关键词：Induced pluripotent stem cells ; Parkinson’s disease ; Parkin ; Oxidative stress ; Mitochondria ; α ; synuclein
• 刊名：Molecular Brain
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：5
• 期：1
• 全文大小：1165KB
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• 作者单位：Yoichi Imaizumi (1)
  Yohei Okada (1) (2)
  Wado Akamatsu (1)
  Masato Koike (3)
  Naoko Kuzumaki (1)
  Hideki Hayakawa (4)
  Tomoko Nihira (4)
  Tetsuro Kobayashi (5)
  Manabu Ohyama (5)
  Shigeto Sato (6)
  Masashi Takanashi (6)
  Manabu Funayama (6) (7)
  Akiyoshi Hirayama (8)
  Tomoyoshi Soga (8)
  Takako Hishiki (9)
  Makoto Suematsu (9)
  Takuya Yagi (10)
  Daisuke Ito (10)
  Arifumi Kosakai (10)
  Kozo Hayashi (11)
  Masanobu Shouji (11)
  Atsushi Nakanishi (11)
  Norihiro Suzuki (10)
  Yoshikuni Mizuno (12)
  Noboru Mizushima (13)
  Masayuki Amagai (5)
  Yasuo Uchiyama (3)
  Hideki Mochizuki (14) (4)
  Nobutaka Hattori (6) (7)
  Hideyuki Okano (1)
  
  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
  
• ISSN：1756-6606

文摘

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.