TY - JOUR
T1 - Establishment of in Vitro FUS-Associated Familial Amyotrophic Lateral Sclerosis Model Using Human Induced Pluripotent Stem Cells
AU - Ichiyanagi, Naoki
AU - Fujimori, Koki
AU - Yano, Masato
AU - Ishihara-Fujisaki, Chikako
AU - Sone, Takefumi
AU - Akiyama, Tetsuya
AU - Okada, Yohei
AU - Akamatsu, Wado
AU - Matsumoto, Takuya
AU - Ishikawa, Mitsuru
AU - Nishimoto, Yoshinori
AU - Ishihara, Yasuharu
AU - Sakuma, Tetsushi
AU - Yamamoto, Takashi
AU - Tsuiji, Hitomi
AU - Suzuki, Naoki
AU - Warita, Hitoshi
AU - Aoki, Masashi
AU - Okano, Hideyuki
N1 - Funding Information:
We thank the members of the Okano laboratory for helpful comments and discussion. The research described in this study was supported by grants from the Program for Intractable Disease Research Utilizing Disease-specific iPS Cells funded by the Japan Science and Technology Agency (JST) / Japan Agency for Medical Research and Development (A-MED) to H.O., Ministry of Health, Labor and Welfare (MHLW) of Japan to H.O., Translational Research Network Program from A-MED to Keio University, the New Energy and Industrial Technology Development Organization (NEDO) , and the Ministry of Education, Science, Sports and Culture (MEXT) (Scientific Research on Innovative Area, a MEXT Grant-in-Aid Project FY2014-2018 “Brain Protein Aging and Dementia Control”). H.O. is a scientific consultant for San Bio Co., Ltd.
Publisher Copyright:
© 2016 The Authors.
PY - 2016/4/12
Y1 - 2016/4/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.stemcr.2016.02.011
DO - 10.1016/j.stemcr.2016.02.011
M3 - Article
C2 - 26997647
AN - SCOPUS:84961226024
SN - 2213-6711
VL - 6
SP - 496
EP - 510
JO - Stem cell reports
JF - Stem cell reports
IS - 4
ER -