I2020T mutant LRRK2 iPSC-derived neurons in the Sagamihara family exhibit increased Tau phosphorylation through the AKT/GSK-3ß signaling pathway

Etsuro Ohta, Tomoko Nihira, Akiko Uchino, Yoichi Imaizumi, Yohei Okada, Wado Akamatsu, Kayoko Takahashi, Hideki Hayakawa, Makiko Nagai, Manabu Ohyama, Masafuchi Ryo, Mieko Ogino, Shigeo Murayama, Akihiko Takashima, Kazutoshi Nishiyama, Yoshikuni Mizuno, Hideki Mochizuki, Fumiya Obata, Hideyuki Okano

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31 Citations (Scopus)

Abstract

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-3ß (GSK-3ß) and high Tau phosphorylation. In addition, the postmortem brain of the patient fromwhomthe 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.

Original languageEnglish
Pages (from-to)4879-4900
Number of pages22
JournalHuman molecular genetics
Volume24
Issue number17
DOIs
Publication statusPublished - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Ohta, E., Nihira, T., Uchino, A., Imaizumi, Y., Okada, Y., Akamatsu, W., Takahashi, K., Hayakawa, H., Nagai, M., Ohyama, M., Ryo, M., Ogino, M., Murayama, S., Takashima, A., Nishiyama, K., Mizuno, Y., Mochizuki, H., Obata, F., & Okano, H. (2015). I2020T mutant LRRK2 iPSC-derived neurons in the Sagamihara family exhibit increased Tau phosphorylation through the AKT/GSK-3ß signaling pathway. Human molecular genetics, 24(17), 4879-4900. https://doi.org/10.1093/hmg/ddv212