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

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

来源：Molecular Brain, 2012, 5(1): 35.

DOI：10.1186/1756-6606-5-35

• Induced pluripotent stem cells
• Parkinson%26apos
• s disease
• Parkin
• Oxidative stress
• Mitochondria
• alpha-synuclein

Background: Parkinson%26apos;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. %26lt;br%26gt;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 alpha-synuclein, alpha-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. %26lt;br%26gt;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.

• 出版日期2012-10-6