| Project/Area Number |
18K15362
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 51030:Pathophysiologic neuroscience-related
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| Research Institution | Nagoya University |
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Principal Investigator |
Yokoi Satoshi 名古屋大学, 医学部附属病院, 医員 (30815460)
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 筋萎縮性側索硬化症 / FUS / シナプス / iPS細胞 / SynGAP / CRISPR/Cas9 / ALS / シナプス機能 |
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| Outline of Final Research Achievements |
FUS is one of the pathogenic RNA-binding proteins for amyotrophic lateral sclerosis (ALS). We reported that FUS stabilizes SynGAP mRNA at its 3'UTR and this mechanism is important for spine maturation and cognitive function in mice model. To elucidate the pathogenesis for ALS, first we explored the exome data of JaCALS cohort and identified the novel mutation in SynGAP 3'UTR at the binding site of FUS. Next we inserted the novel mutation to hiPSC (201B7) by CRISPR/Cas9. Then motor neurons were differentiated from edited hiPSCs and are cultured for 4 weeks. We identified the number of spines decreased in motor neurons with the novel mutation. Pull-down assay revealed that SynGAP 3'UTR mutation causes an increase of FUS binding. The novel SynGAP 3'UTR mutation causes an increase of FUS binding, resulting decreased spine number. The aberrant FUS-SynGAP mRNA regulation might be pathogenic for ALS.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、シナプス蛋白の異常が筋萎縮性側索硬化症を引き起こす可能性が初めて見いだされた。変異を有した運動神経の詳細なRNA代謝異常を同定し、今まで不明であった筋萎縮性側索硬化症がなぜ起こるかを証明していく。また、RNA代謝異常やシナプス異常を是正する化合物開発のモデルが構築できた。さらなる検討により、筋萎縮性側索硬化症に対する治療薬開発に発展させることが可能である。
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