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ID 118915
Title Alternative
A SYNGAP1 Variant in ALS Causes Spine Loss
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
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
Keywords
amyotrophic lateral sclerosis
antisense oligonucleotides
dendritic spine
hnRNPK
iPSC-derived motor neuron
SYNGAP1
Content Type
Journal Article
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.
Journal Title
The Journal of Neuroscience
ISSN
15292401
02706474
NCID
AA10620404
Publisher
Society for Neuroscience
Volume
42
Issue
47
Start Page
8881
End Page
8896
Published Date
2022-10-19
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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DOI (Published Version)
URL ( Publisher's Version )
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language
eng
TextVersion
Publisher
departments
University Hospital