title: Establishment of In Vitro FUS-Associated Familial Amyotrophic Lateral Sclerosis Model Using Human Induced Pluripotent Stem Cells.
abstract: Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disorder. Although its neuropathology is well understood, the cellular and molecular mechanisms are yet to be elucidated due to limitations in the currently available human genetic data. In this study, we generated induced pluripotent stem cells (iPSC) from two familial ALS (FALS) patients with a missense mutation in the fused-in sarcoma (FUS) gene carrying the heterozygous FUS H517D mutation, and isogenic iPSCs with the homozygous FUS H517D mutation by genome editing technology. These cell-derived motor neurons mimicked several neurodegenerative phenotypes including mis-localization of FUS into cytosolic and stress granules under stress conditions, and cellular vulnerability. Moreover, exon array analysis using motor neuron precursor cells (MPCs) combined with CLIP-seq datasets revealed aberrant gene expression and/or splicing pattern in FALS MPCs. These results suggest that iPSC-derived motor neurons are a useful tool for analyzing the pathogenesis of human motor neuron disorders.
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ichiyanagi
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Fujimori
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachidori, Chuo-ku, Niigata 951-8510, Japan. Electronic address: myano@med.niigata-u.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Yano
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Ishihara-Fujisaki
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Sone
authors.affiliation: Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Akiyama
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Neurology, Aichi Medical University School of Medicine, 1-1 Yazako Karimata, Nagakute, Aichi 480-1195, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Center for Genomic and Regenerative Medicine, Graduated School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Wado
authors.initials: W
authors.lastname: Akamatsu
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nishimoto
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Ishihara
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashihiroshima, Hiroshima 739-8526, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Sakuma
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashihiroshima, Hiroshima 739-8526, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Tsuiji
authors.affiliation: Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Warita
authors.affiliation: Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: hidokano@a2.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D005192:Family Health; D005260:Female; D000072669:Gene Editing; D020869:Gene Expression Profiling / Q000379:methods; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D010375:Pedigree; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: C000599550:FUS protein, human; D034702:RNA-Binding Protein FUS