title: Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons.
abstract: Mutations in the gene MAPT encoding tau, a microtubules-associated protein, cause a subtype of familial neurodegenerative disorder, known as frontotemporal lobar degeneration tauopathy (FTLD-Tau), which presents with dementia and is characterized by atrophy in the frontal and temporal lobes of the brain. Although induced pluripotent stem cell (iPSC) technology has facilitated the investigation of phenotypes of FTLD-Tau patient neuronal cells in vitro, it remains unclear how FTLD-Tau patient neurons degenerate. Here, we established neuronal models of FTLD-Tau by Neurogenin2-induced direct neuronal differentiation from FTLD-Tau patient iPSCs. We found that FTLD-Tau neurons, either with an intronic MAPT mutation or with an exonic mutation, developed accumulation and extracellular release of misfolded tau followed by neuronal death, which we confirmed by correction of the intronic mutation with CRISPR/Cas9. FTLD-Tau neurons showed dysregulation of the augmentation of Ca2+transients evoked by electrical stimulation. Chemogenetic or pharmacological control of neuronal activity-relevant Ca2+influx by the introduction of designer receptors exclusively activated by designer drugs (DREADDs) or by the treatment with glutamate receptor blockers attenuated misfolded tau accumulation and neuronal death. These data suggest that neuronal activity may regulate neurodegeneration in tauopathy. This FTLD-Tau model provides mechanistic insights into tauopathy pathogenesis and potential avenues for treatments.
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Imamura
authors.affiliation: Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
authors.forename: Naruhiko
authors.initials: N
authors.lastname: Sahara
authors.affiliation: Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Kanaan
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Tsukita
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Neurology, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kutoku
authors.affiliation: Department of Neurology, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ohsawa
authors.affiliation: Department of Neurology, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Sunada
authors.affiliation: Division of Molecular and Developmental Biology, National Institute of Genetics and Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies), Mishima, Shizuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: Akitsu
authors.initials: A
authors.lastname: Hotta
authors.affiliation: Department of Biological Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yawata
authors.affiliation: Department of Biological Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Watanabe
authors.affiliation: Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.affiliation: Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Inoue
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D057174:Frontotemporal Lobar Degeneration / Q000503:physiopathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000473:pathology*; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D017510:Protein Folding; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; D002118:Calcium