title: Modeling the early phenotype at the neuromuscular junction of spinal muscular atrophy using patient-derived iPSCs.
abstract: Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations of the survival of motor neuron 1 (SMN1) gene. In the pathogenesis of SMA, pathological changes of the neuromuscular junction (NMJ) precede the motor neuronal loss. Therefore, it is critical to evaluate the NMJ formed by SMA patients' motor neurons (MNs), and to identify drugs that can restore the normal condition. We generated NMJ-like structures using MNs derived from SMA patient-specific induced pluripotent stem cells (iPSCs), and found that the clustering of the acetylcholine receptor (AChR) is significantly impaired. Valproic acid and antisense oligonucleotide treatment ameliorated the AChR clustering defects, leading to an increase in the level of full-length SMN transcripts. Thus, the current in vitro model of AChR clustering using SMA patient-derived iPSCs is useful to dissect the pathophysiological mechanisms underlying the development of SMA, and to evaluate the efficacy of new therapeutic approaches.
authors: Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors: Michiko
authors: M
authors: Yoshida
authors: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Shiho
authors: S
authors: Kitaoka
authors: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors: Naohiro
authors: N
authors: Egawa
authors: Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Mayu
authors: M
authors: Yamane
authors: Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Ryunosuke
authors: R
authors: Ikeda
authors: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Kayoko
authors: K
authors: Tsukita
authors: Department of Reprogramming Science, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Naoki
authors: N
authors: Amano
authors: Department of Reprogramming Science, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Akira
authors: A
authors: Watanabe
authors: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors: Masafumi
authors: M
authors: Morimoto
authors: Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Jun
authors: J
authors: Takahashi
authors: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors: Hajime
authors: H
authors: Hosoi
authors: Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Tatsutoshi
authors: T
authors: Nakahata
authors: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors: Haruhisa
authors: H
authors: Inoue
authors: Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. Electronic address: msaito@cira.kyoto-u.ac.jp.
authors: Megumu K
authors: MK
authors: Saito
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002460:Cell Line; D018920:Coculture Techniques; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D060172:Morpholinos / Q000494:pharmacology; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D060172:Morpholinos; D014635:Valproic Acid