Functional-structural relationship of liquid-liquid phase separation caused by ALS-causing proteins and its pathological significance.
| Project/Area Number |
20H03593
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 52020:Neurology-related
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
早水 裕平 東京工業大学, 物質理工学院, 准教授 (80443216)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2022: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2021: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2020: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
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| Keywords | 液液相分離 / 筋萎縮性側索硬化症 / C9ORF72 / TDP-43 / ALS / 非膜性オルガネラ / LLPS / C9orf72 |
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| Outline of Research at the Start |
真核生物は細胞内の特定の部位において生体高分子のやわらかな凝集を作り、生命活動を効率よく進める。この凝集の形成過程に液液相分離(LLPS)と呼ばれる現象が関与することが明らかとなってきた。近年神経変性疾患の様々な原因蛋白がLLPSを起こすことが報告され、特に筋萎縮性側索硬化症(ALS)においてはC9orf72、FUS、TDP43など多数のRNA結合原因蛋白がLLPSを起こす。本研究はこれらLLPSを起こすALS原因蛋白に対して集中的な構造機能解析を行い、LLPS制御の分子機構を明らかにすることで、LLPS異常によるALS発症解明の端緒となる知見を得ることを目指す。
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| Outline of Final Research Achievements |
ALS-related proteins such as C9ORF72 dipeptide repeat proteins and TDP-43 are thought to contribute to ALS pathogenesis by disturbing phase separation homeostasis, but their molecular mechanisms have remained unclear. In this study, we analyzed why C9ORF72-derived poly(PR) is toxic by combining various structural variants, multi-omics analyses, and in silico analysis, and found that although the insertion of Pro between Arg is disadvantageous in terms of binding energy, it promotes multivalent binding and enhanced phase separation, resulting in toxicity.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の成果により、C9ORF72由来ジペプチドの機能構造連関が初めて明らかとなった。本研究を応用することで、C9ORF72-poly(PR)の毒性機構を理解し、さらに相分離異常を標的とした新規治療法の開発にもつながる可能性がある。また、本研究は非膜性オルガネラの形成機構など広く科学分野へ寄与する可能性がある。研究生はは論文の出版や学会発表を通じて学術界で知見を共有し、さらに一般社会へ還元される。
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Report
(4 results)
Research Products
(27 results)
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[Journal Article] Nuclear microRNAs release paused Pol II via the DDX21-CDK9 complex2022
Author(s)
Shin-Ichiro Ohno, Keiki Oikawa, Toshiaki Tsurui, Yuichirou Harada, Kana Ono, Mizumo Tateishi, Aashiq Mirza, Masakatsu Takanashi, Kosuke Kanekura, Kumiko Nagase, Yoshihisa Shimada, Yujin Kudo, Norihiko Ikeda, Takahiro Ochiya, Xiaozhong Wang , Masahiko Kuroda
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Journal Title
Cell Reports
Volume: 12;39(2)
Issue: 2
Pages: 110673-110673
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Phase separation and toxicity of C9orf72 poly(PR) depends on alternate distribution of arginine.2021
Author(s)
Chen C, Yamanaka Y, Ueda K, Li P, Miyagi T, Harada Y, Tezuka S, Narumi S, Sugimoto M, Kuroda M, Hayamizu Y, Kanekura K.
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Journal Title
J Cell Biol.
Volume: 220
Issue: 11
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Expression of L-type amino acid transporter 1 is a poor prognostic factor for Non-Hodgkin's lymphoma.2021
Author(s)
Jigjidkhorloo N, Kanekura K, Matsubayashi J, Akahane D, Fujita K, Oikawa K, Kurata A, Takanashi M, Endou H, Nagao T, Gotoh A, Norov O, Kuroda M.
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Journal Title
Sci Rep.
Volume: 11(1)
Issue: 1
Pages: 21638-21638
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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