Research
Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue
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
Molecular Brain 2012, 5:35 doi:10.1186/1756-6606-5-35
Published: 6 October 2012Abstract
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.
