TY - JOUR
T1 - The SYNGAP1 3'UTR Variant in ALS Patients Causes Aberrant SYNGAP1 Splicing and Dendritic Spine Loss by Recruiting HNRNPK
AU - Yokoi, Satoshi
AU - Ito, Takuji
AU - Sahashi, Kentaro
AU - Nakatochi, Masahiro
AU - Nakamura, Ryoichi
AU - Tohnai, Genki
AU - Fujioka, Yusuke
AU - Ishigaki, Shinsuke
AU - Udagawa, Tsuyoshi
AU - Izumi, Yuishin
AU - Morita, Mitsuya
AU - Kano, Osamu
AU - Oda, Masaya
AU - Sone, Takefumi
AU - Okano, Hideyuki
AU - Atsuta, Naoki
AU - Katsuno, Masahisa
AU - Okada, Yohei
AU - Sobue, Gen
N1 - Funding Information:
This work was supported by Japan Agency for Medical Research and Development (AMED) Grants JP22ek0109434, JP19ek0109243, JP22bm0804003, JP22bm0804020, 22ak0101111, 22ek0109492, and 24wm0425009; Japan Society for the Promotion of Science (JSPS) KAKENHI Grants JP20K16489, JP19H03576, and JP22H02988; the Hori Sciences & Arts Foundation; and the Japan and Kanae Foundation for the promotion of medical science, Japan. This work is partially supported by Nagoya University Research Fund. We thank Hiroyuki Mizuguchi for the kind gift of plasmids, Shinya Yamanaka for the kind gift of human iPSCs (201B7), and Kentaro Taki for technical support with LC/MS/MS in the laboratory of the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine.
Funding Information:
This work was supported by Japan Agency for Medical Research and Development (AMED) Grants JP22ek0109434, JP19ek0109243, JP22bm0804003, JP22bm0804020, 22ak0101111, 22ek0109492, and 24wm0425009; Japan Society for the Promotion of Science (JSPS) KAKENHI Grants JP20K16489, JP19H03576, and JP22H02988; the Hori Sciences & Arts Foundation; and the Japan and Kanae Foundation for the promotion of medical science, Japan. This work is partially supported by Nagoya University Research Fund. We thank Hiroyuki Mizuguchi for the kind gift of plasmids, Shinya Yamanaka for the kind gift of human iPSCs (201B7), and Kentaro Taki for technical support with LC/MS/MS in the laboratory of the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine. The authors declare no competing financial interests.
Publisher Copyright:
© 2022 Yokoi et al.
PY - 2022/11/23
Y1 - 2022/11/23
N2 - 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.
AB - 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.
KW - amyotrophic lateral sclerosis
KW - antisense oligonucleotides
KW - dendritic spine
KW - hnRNPK
KW - iPSC-derived motor neuron
KW - SYNGAP1
UR - http://www.scopus.com/inward/record.url?scp=85142939824&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85142939824&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0455-22.2022
DO - 10.1523/JNEUROSCI.0455-22.2022
M3 - Article
C2 - 36261283
AN - SCOPUS:85142939824
SN - 0270-6474
VL - 42
SP - 8881
EP - 8896
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 47
ER -