| Project/Area Number |
18K07361
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 51030:Pathophysiologic neuroscience-related
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| Research Institution | International University of Health and Welfare (2020)
Hokkaido University (2018-2019) |
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Principal Investigator |
Nakaya Tadashi 国際医療福祉大学, 福岡薬学部, 講師 (50374559)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | ALS / FUS / R495X / メチル化 / 凝集体 / 筋萎縮性側索硬化症 / RNA結合 / RNA |
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| Outline of Final Research Achievements |
FUS is one of causative factors of Amyotrophic lateral sclerosis (ALS). To gain insight into the molecular mechanism underlying its ability to form aggregates in neuron, an ALS associated FUS mutant, R495X, was employed and subject for analyses in this study. Focusing on five intramolecular protein domains in FUS, R495X deleted each domain with EGFP tag was prepared and expressed in mouse ES cell derived neurons. EGFP-R495X formed intracellular aggregates as expected, while deletion of any of Gly-rich, RGG1 or RGG2 showed no aggregates in neurons. Furthermore, facilitation of arginine methylation on EGFP-R495X significantly increased the number of cells with intracellular aggregates, while reduction of methylation significantly decreased them. These results indicate that methylation in the domains regulates the aggregate formation ability of FUS in neuron.
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| Academic Significance and Societal Importance of the Research Achievements |
筋萎縮性側索硬化症の原因タンパク質の一部は、患者の神経細胞で異常な凝集体を形成することから、凝集体の形成機構が疾患発症と深く関わると考えられたが、その機構の詳細は不明であった。本研究では、原因因子の一つFUSにおいて、分子内のメチル化が凝集に必要であることを見出した。このことはFUSが原因となる神経疾患においてメチル化の阻害が治療標的となりうることを示唆する。
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