title: I2020T mutant LRRK2 iPSC-derived neurons in the Sagamihara family exhibit increased Tau phosphorylation through the AKT/GSK-3β signaling pathway.
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-3β (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. 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.
authors.affiliation: R & D Center for Cell Design, Institute for Regenerative Medicine and Cell Design, Kitasato University School of Allied Health Sciences, Kanagawa, Japan, Division of Clinical Immunology, Graduate School of Medical Sciences, Department of Physiology.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ohta
authors.affiliation: Department of Neuro-Regenerative Medicine, Department of Physiology.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nihira
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kitasato University, Kanagawa, Japan, Department of the Brain Bank for Aging Research.
authors.forename: Akiko
authors.initials: A
authors.lastname: Uchino
authors.affiliation: Department of Physiology.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Imaizumi
authors.affiliation: Department of Physiology, Department of Neurology, Aichi Medical University School of Medicine, Aichi, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Physiology, Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Wado
authors.initials: W
authors.lastname: Akamatsu
authors.affiliation: Department of Medical Laboratory, Kitasato University Hospital, Kanagawa, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Neuro-Regenerative Medicine.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayakawa
authors.affiliation: Department of Neurology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Nagai
authors.affiliation: Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Ohyama
authors.affiliation: Department of Neurology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Masafuchi
authors.initials: M
authors.lastname: Ryo
authors.affiliation: Department of Neurology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Mieko
authors.initials: M
authors.lastname: Ogino
authors.affiliation: Department of the Brain Bank for Aging Research, Department of Neurology, Department of Bioresource Center (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.affiliation: Department of Neurobiology, National Center for Geriatrics and Gerontology, Obu, Japan and.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takashima
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kitasato University, Kanagawa, Japan, Department of Neurology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Nishiyama
authors.affiliation: Department of Neuro-Regenerative Medicine.
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Mizuno
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: R & D Center for Cell Design, Institute for Regenerative Medicine and Cell Design, Kitasato University School of Allied Health Sciences, Kanagawa, Japan, Division of Clinical Immunology, Graduate School of Medical Sciences.
authors.forename: Fumiya
authors.initials: F
authors.lastname: Obata
authors.affiliation: Department of Physiology, hidokano@a2.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D004298:Dopamine