Study of interaction between TDP-43 and RNA guanine quadruplex and its disruption
| Project/Area Number |
17K07291
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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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| Research Field |
Molecular biology
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| Research Institution | Hosei University |
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Principal Investigator |
Ishiguro Akira 法政大学, マイクロ・ナノテクノロジー研究センター, 研究員 (70373264)
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| Project Period (FY) |
2017-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | RNA / グアニン四重鎖 / 筋萎縮性側索硬化症 / TDP-43 / 局所翻訳 / FUS / 神経変性疾患 / 前頭側頭葉変性症 / RNA立体構造 / mRNA輸送 / ALS / ローカルトランスレーション |
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| Outline of Final Research Achievements |
Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD) are characterized by the progressive degeneration of nerve cells in the brain and spinal cord. TDP-43 is the major pathogenic protein of ALS and FTLD. Previously I identified the involvement of TDP-43 in interaction with G4 (G-quadruplex)-containing RNA for long-distance transport in neurons. For the molecular dissection of TDP-43, I analyzed ALS-linked ten mutant TDP-43 proteins and detected all ten mutants with reduced activity of G4-RNA-binding. Furthermore, I identified that TDP-43 binds to cover the entire parallel-stranded G4 and maintains a stable conformation. These results suggested that the altered interaction between G4-RNAs and mutant proteins is somehow connected with the pathogenesis of ALS and FTLD.
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| Academic Significance and Societal Importance of the Research Achievements |
ALSは未だ有効な治療薬や治療法の無い神経変性疾患である。これまで主に変性タンパク質の蓄積による毒性が原因とされ、多くの研究が進められて来た。しかし、結局未だ変性タンパク質の毒性は証明されず、高齢健常者の３割で同様の蓄積が認められるに至り「タンパク質毒性仮説」の矛盾点が表面化している。本研究では責任タンパク質の機能に焦点を当て、その破綻が細胞機能阻害を引き起こす事を証明した。本研究の成果は今後の研究の基礎として、他グアニン四重鎖結合タンパク質の機能解析や、さらには医薬シーズとしてのグアニン四重鎖結合化合物の捜索・開発にも直結する。
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Report
(5 results)
Research Products
(16 results)
