Development of zebrafish ALS model for understanding and regulation of TDP-43 neurotoxicity
| Project/Area Number |
16K07045
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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 |
Nerve anatomy/Neuropathology
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| Research Institution | National Institute of Genetics |
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Principal Investigator |
ASAKAWA Kazuhide 国立遺伝学研究所, 遺伝形質研究系, 助教 (30515664)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
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| Keywords | ALS / 運動ニューロン / TDP-43 / PI3K / mTOR / 神経変性 / タンパク質恒常性 / ゼブラフィッシュ / PI3キナーゼ / オートファジー / 脊髄運動ニューロン / CRISPR-Cas9 / カルシウムイメージング / CaP / フローサイトメトリー |
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| Outline of Final Research Achievements |
TAR DNA-binding protein 43 (TDP-43) is s a major component of the cytoplasmic inclusions accumulating in degenerating motor neurons in amyotrophic lateral sclerosis (ALS). In this study, we show that both overexpression and knockout of TDP-43 result in motor axon outgrowth defects. We further demonstrate that the targeted activation of PI3 kinase effectively restores the axonal outgrowth in both TDP-43 overexpression and knockout conditions. The PI3 kinase-dependent rescue is cancelled by the mTOR inhibitor rapamycin treatment. Thus, our results suggest that abrogation of TDP-43 proteostasis halts axon outgrowth, which can be rescued through the activation of PI3K-mTOR pathway. Modulation of PI3K-mTOR pathway could offer a potential therapeutic strategy for ALS.
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| Academic Significance and Societal Importance of the Research Achievements |
ヘテロリボ核タンパク質TDP-43の過度の増量や減少（TDP-43タンパク質恒常性の破綻）によって運動ニューロンの成長が阻害されることを示し、さらに、この成長阻害をレスキューすることのできる生物学的経路を見出した。これらの新しい知見は、ALSの病態メカニズムの理解と、治療戦略の構築に貢献すると期待される。
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Report
(4 results)
Research Products
(26 results)
