Journal
MOLECULAR BRAIN
Volume 5, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1756-6606-5-35
Keywords
Induced pluripotent stem cells; Parkinson's disease; Parkin; Oxidative stress; Mitochondria; alpha-synuclein
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Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Japan Science and Technology Agency (JST)
- Japan Society for the Promotion of Science (JSPS)
- Keio Kanrinmaru Project
- MEXT
- Grants-in-Aid for Scientific Research [23790238, 24651265, 23659102, 23618010, 23129506, 23689017, 23390041, 23650194] Funding Source: KAKEN
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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 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. 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.
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