Pathological analysis of hereditary Parkinson's disease using induced pluripotent stem cells

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K06777
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Kitasato University
• Principal Investigator: OHTA ETSURO 北里大学, 医療衛生学部, 講師 (60508042)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: パーキンソン病 / LRRK2 / iPS細胞 / TAU / ゲノム編集 / PARK8

Outline of Final Research Achievements

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 harboring the I2020T mutation. In the present study, to elucidate the mechanism of neurodegeneration in PD caused by LRRK2, we generated iPS cells (iPSC) derived from fibroblasts of PD patients. We found that patient 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 GSK-3β 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.

Free Research Field

細胞生物学