Journal
HUMAN MOLECULAR GENETICS
Volume 24, Issue 17, Pages 4879-4900Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv212
Keywords
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Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Japan Science and Technology Agency (JST)
- Japan Agency for Medical Research and Development (AMED)
- Brain Science Foundation
- MEXT [15H01565]
- Kitasato University School of Allied Health Sciences [2012-1006, 2013-1005, 2014-1007]
- Kitasato University
- [15K06777]
- Grants-in-Aid for Scientific Research [15H01565, 15K06777, 26117007] Funding Source: KAKEN
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Leucine-rich repeat kinase 2 (LRRK2) is the causative molecule of the autosomal dominant hereditary form of Parkinson's disease (PD), PARK8, which was originally defined in a study of a Japanese family (the Sagamihara family) harboring the I2020T mutation in the kinase domain. Although a number of reported studies have focused on cell death mediated by mutant LRRK2, details of the pathogenetic effect of LRRK2 still remain to be elucidated. In the present study, to elucidate the mechanism of neurodegeneration in PD caused by LRRK2, we generated induced pluripotent stem cells (iPSC) derived from fibroblasts of PD patients with I2020T LRRK2 in the Sagamihara family. We found that I2020T mutant LRRK2 iPSC-derived neurons released less dopamine than control-iPSC-derived neurons. Furthermore, we demonstrated that patient iPSC-derived neurons had a lower phospho-AKT level than control-iPSC-derived neurons, and that the former showed an increased incidence of apoptosis relative to the controls. Interestingly, patient iPSC-derived neurons exhibited activation of glycogen synthase kinase-3 beta (GSK-3 beta) and high Tau phosphorylation. In addition, the postmortem brain of the patient from whom the iPSC had been established exhibited deposition of neurofibrillary tangles as well as increased Tau phosphorylation in neurons. These results suggest that I2020T LRRK2-iPSC could be a promising new tool for reproducing the pathology of PD in the brain caused by the I2020T mutation, and applicable as a model in studies of targeted therapeutics.
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