The SYNGAP1 3'UTR Variant in ALS Patients Causes Aberrant SYNGAP1 Splicing and Dendritic Spine Loss by Recruiting HNRNPK

Satoshi Yokoi, Takuji Ito, Kentaro Sahashi, Masahiro Nakatochi, Ryoichi Nakamura, Genki Tohnai, Yusuke Fujioka, Shinsuke Ishigaki, Tsuyoshi Udagawa, Yuishin Izumi, Mitsuya Morita, Osamu Kano, Masaya Oda, Takefumi Sone, Hideyuki Okano, Naoki Atsuta, Masahisa Katsuno, Yohei Okada, Gen Sobue

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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 39 untranslated region (UTR) and maintains spine maturation. To elucidate the pathologic roles of this mechanism in ALS patients, we identified the SYNGAP1 39UTR 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 c 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.

Original languageEnglish
Pages (from-to)8881-8896
Number of pages16
JournalJournal of Neuroscience
Volume42
Issue number47
DOIs
Publication statusPublished - 2022 Nov 23

Keywords

  • SYNGAP1
  • amyotrophic lateral sclerosis
  • antisense oligonucleotides
  • dendritic spine
  • hnRNPK
  • iPSC-derived motor neuron

ASJC Scopus subject areas

  • General Neuroscience

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