@article{e53798c696c543dbbc8663543365d918,
title = "Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue",
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, Mitochondria, Oxidative stress, Parkin, Parkinson's disease, α-synuclein",
author = "Yoichi Imaizumi and Yohei Okada and Wado Akamatsu and Masato Koike and Naoko Kuzumaki and Hideki Hayakawa and Tomoko Nihira and Tetsuro Kobayashi and Manabu Ohyama and Shigeto Sato and Masashi Takanashi and Manabu Funayama and Akiyoshi Hirayama and Tomoyoshi Soga and Takako Hishiki and Makoto Suematsu and Takuya Yagi and Daisuke Ito and Arifumi Kosakai and Kozo Hayashi and Masanobu Shouji and Atsushi Nakanishi and Norihiro Suzuki and Yoshikuni Mizuno and Noboru Mizushima and Masayuki Amagai and Yasuo Uchiyama and Hideki Mochizuki and Nobutaka Hattori and Hideyuki Okano",
note = "Funding Information: We would like to thank S. Yamanaka (CiRA) for the 201B7 iPSCs; N. Nakatsuji (Kyoto University) for the KhES cells; N. Izawa, S. Banno, Y. Matsuzaki, M. Fujiwara, Y. Nagahata, N. Hirose (Keio University), C. Kishi (Tokyo Medical and Dental University), M. Ogino, S. Miyakawa, (Kitasato University) and G. Takata (GE Healthcare Biosciences) for technical assistance and suggestions. This work was supported by the Project for the Realization of Regenerative Medicine and Support for the Core Institutes for iPS cell research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) to H.O., Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project from Japan Science and Technology Agency (JST) to M.S., a Grant-in-Aid from the Japan Society for the Promotion of Science (JSPS) to W.A. and Y.O., the Keio Kanrinmaru Project and a Grant-in-Aid for Scientific Research on Innovative Areas to Y.O., a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the MEXT to Y. O. and Y. I., a Grant-in-Aid for Encouragement of Young Medical Scientists from Keio University and the Japan Society for the Promotion of Science Fellows to Y.I., and a Grant-in-Aid for the Global COE Program at Keio University.",
year = "2012",
doi = "10.1186/1756-6606-5-35",
language = "English",
volume = "5",
journal = "Molecular brain",
issn = "1756-6606",
publisher = "BioMed Central",
number = "1",
}
