ID | 118915 |
Title Alternative | A SYNGAP1 Variant in ALS Causes Spine Loss
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Author |
Yokoi, Satoshi
Nagoya University
Ito, Takuji
Aichi Medical University
Sahashi, Kentaro
Nagoya University
Nakatochi, Masahiro
Nagoya University
Nakamura, Ryoichi
Nagoya University|Aichi Medical University
Tohnai, Genki
Aichi Medical University
Fujioka, Yusuke
Nagoya University
Ishigaki, Shinsuke
Nagoya University
Udagawa, Tsuyoshi
Nagoya City University
Izumi, Yuishin
Tokushima University
Tokushima University Educator and Researcher Directory
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Morita, Mitsuya
Jichi Medical University
Kano, Osamu
Toho University
Oda, Masaya
Vihara Hananosato Hospital
Sone, Takefumi
Keio University
Okano, Hideyuki
Keio University
Atsuta, Naoki
Nagoya University|Aichi Medical University
Katsuno, Masahisa
Nagoya University
Okada, Yohei
Aichi Medical University
Sobue, Gen
Nagoya University|Aichi Medical University
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Keywords | amyotrophic lateral sclerosis
antisense oligonucleotides
dendritic spine
hnRNPK
iPSC-derived motor neuron
SYNGAP1
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Content Type |
Journal Article
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Description | Fused in sarcoma (FUS) is a pathogenic RNA-binding protein in amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilizes Synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3′ untranslated region (UTR) and maintains spine maturation. To elucidate the pathologic roles of this mechanism in ALS patients, we identified the SYNGAP1 3′UTR variant rs149438267 in seven (four males and three females) out of 807 ALS patients at the FUS binding site from a multicenter cohort in Japan. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, increased isoform α1 levels, and decreased isoform γ levels, which caused dendritic spine loss. Moreover, the SYNGAP1 variant excessively recruited FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK), and antisense oligonucleotides (ASOs) blocking HNRNPK altered aberrant splicing and ameliorated dendritic spine loss. These data suggest that excessive recruitment of RNA-binding proteins, especially HNRNPK, as well as changes in SYNGAP1 isoforms, are crucial for spine formation in motor neurons.
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Journal Title |
The Journal of Neuroscience
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ISSN | 15292401
02706474
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NCID | AA10620404
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Publisher | Society for Neuroscience
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Volume | 42
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Issue | 47
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Start Page | 8881
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End Page | 8896
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Published Date | 2022-10-19
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Rights | This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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language |
eng
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Publisher
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departments |
University Hospital
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