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Development of zebrafish ALS model for understanding and regulation of TDP-43 neurotoxicity

Research Project

Project/Area Number 16K07045
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Nerve anatomy/Neuropathology
Research InstitutionNational Institute of Genetics

Principal Investigator

ASAKAWA Kazuhide  国立遺伝学研究所, 遺伝形質研究系, 助教 (30515664)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
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)
KeywordsALS / 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
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.

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。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (26 results)

All 2019 2018 2017 2016 Other

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 4 results,  Acknowledgement Compliant: 1 results) Presentation (19 results) (of which Int'l Joint Research: 7 results,  Invited: 4 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Protocadherin-mediated cell repulsion controls the central topography and efferent projections of the abducens nucleus.2018

    • Author(s)
      Asakawa, K, and Kawakami, K.
    • Journal Title

      Cell Reports

      Volume: 24 Issue: 6 Pages: 1562-1572

    • DOI

      10.1016/j.celrep.2018.07.024

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Protocadherin-mediated cell repulsion controls the central topography and efferent projections of the abducens nucleus2018

    • Author(s)
      Kazuhide Asakawa
    • Journal Title

      bioRxiv

      Volume: .

    • DOI

      10.1101/283473

    • Related Report
      2017 Research-status Report
    • Open Access
  • [Journal Article] Glycine-alanine dipeptide repeat protein contributes to toxicity in a zebrafish model of C9orf72 associated neurodegeneration.2017

    • Author(s)
      Yu Ohki, Andrea Wenninger-Weinzierl, Alexander Hruscha, Kazuhide Asakawa, Koichi Kawakami, Christian Haass, Dieter Edbauer and Bettina Schmid
    • Journal Title

      Molecular Neurodegeneration

      Volume: 12 Issue: 1 Pages: 6-6

    • DOI

      10.1186/s13024-016-0146-8

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Visualization of Neuregulin 1 ectodomain shedding reveals its local processing in vitro and in vivo.2016

    • Author(s)
      Kamezaki A, Sato F, Aoki K, Asakawa K, Kawakami K, Matsuzaki F, Sehara-Fujiwara A.
    • Journal Title

      Scientific Reports

      Volume: 6 Issue: 1 Pages: 28873-28873

    • DOI

      10.1038/srep28873

    • NAID

      120005819488

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 眼球運動経路の構造と生理のイメージング2019

    • Author(s)
      浅川和秀
    • Organizer
      第13回バイオイメージングフォーラム&基礎生物学研究所重点共同利用合同シンポジウム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Optogenetic enhancement of TDP-43 intermolecular interaction triggers its cytoplasmic mislocalization and inhibits axon outgrowth of spinal motor neurons2018

    • Author(s)
      Kazuhide Asakawa
    • Organizer
      29th International symposium on ALS/MND
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 光照射によるALS病態の再現にむけて2018

    • Author(s)
      浅川和秀
    • Organizer
      The 41st Annual Meeting of the Molecular Biology Society of Japan
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 光照射によるALS病態の再現にむけて2018

    • Author(s)
      浅川和秀
    • Organizer
      第4回ゼブラフィッシュ・メダカ創薬研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Optogenetic enhancement of TDP-43 intermolecular interaction triggers its cytoplasmic mislocalization and inhibits axon outgrowth of spinal motor neurons2018

    • Author(s)
      Kazuhide Asakawa
    • Organizer
      Neuroscience 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Optogenetic enhancement of TDP-43 intermolecular interaction triggers its cytoplasmic mislocalization and inhibits axon outgrowth of spinal motor neurons2018

    • Author(s)
      Kazuhide Asakawa
    • Organizer
      5th RNA metabolism in Neurological Disease Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Motor neurons become attractable by repulsion2018

    • Author(s)
      浅川 和秀
    • Organizer
      25th Japanese Medaka and Zebrafish Meeting
    • Related Report
      2018 Annual Research Report
  • [Presentation] TDP-43タンパク質恒常性の崩壊によって誘導される脊髄運動ニューロンの神経萎縮は、PI3Kα/mTOR経路の活性化によってレスキューされる2018

    • Author(s)
      浅川 和秀
    • Organizer
      第41回日本神経科学大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] PI3Ka/mTOR pathway rescues TDP-43 toxicity in the spinal motor neuron in zebrafish2017

    • Author(s)
      Kazuhide Asakawa
    • Organizer
      28th International Symposium on ALS/MND
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 精神疾患リスク因子VIPL/LMAN2Lレクチンのゼブラフィッシュ変異体が示す体性感覚反射の異常2017

    • Author(s)
      浅川和秀
    • Organizer
      ConBio2017
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Activation of PI3K/mTOR pathway alleviates TDP-43-induced axonopathy in the spinal motor neuron in a zebrafish ALS mode2017

    • Author(s)
      Kazuhide Asakawa
    • Organizer
      Neuroscience 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] ゼブラフィッシュALSモデルを用いたTDP-43毒性の緩和法の探索2017

    • Author(s)
      浅川和秀
    • Organizer
      第3回 ゼブラフィッシュ創薬研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] ゼブラフィッシュALSモデルを用いたTDP-43毒性の緩和法の探索2017

    • Author(s)
      浅川和秀
    • Organizer
      情報計算化学生物学会2017年大会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] PI3K/mTOR pathway rescues TDP-43 toxicity in the spinal motor neuron in a zebrafish ALS model2017

    • Author(s)
      浅川和秀
    • Organizer
      第23回 小型魚類研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] PI3 kinase activation alleviates TDP-43-induced axonopathy in the spinal motor neuron in a zebrafish ALS model2016

    • Author(s)
      Kazuhide Asakawa
    • Organizer
      27th International Symposium on ALS/MND
    • Place of Presentation
      Dublin, Ireland
    • Year and Date
      2016-12-07
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] PI3K activation alleviates TDP-43-induced axonopathy in a zebrafish ALS model2016

    • Author(s)
      Kazuhide Asakawa
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Research-status Report
  • [Presentation] PI3K activation alleviates TDP-43-induced axonopathy in a zebrafish ALS model2016

    • Author(s)
      Kazuhide Asakawa
    • Organizer
      4th RNA Metabolism in Neurological Disease
    • Place of Presentation
      San Diego, USA
    • Year and Date
      2016-11-10
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] PI3K activation alleviates TDP-43-induced axonopathy in a zebrafish ALS model2016

    • Author(s)
      Kazuhide Asakawa
    • Organizer
      The 22nd Japanese Medaka and Zebrafish Meeting
    • Place of Presentation
      岡崎
    • Year and Date
      2016-08-20
    • Related Report
      2016 Research-status Report
  • [Presentation] PI3キナーゼ経路の活性化はTDP-43によって誘導される脊髄運動ニューロンの機能障害を緩和する2016

    • Author(s)
      Kazuhide Asakawa
    • Organizer
      第39回日本神経科学大会
    • Place of Presentation
      横浜
    • Year and Date
      2016-07-20
    • Related Report
      2016 Research-status Report
  • [Remarks] ResearchMap

    • URL

      https://researchmap.jp/kazuhideasakawa/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 浅川和秀HP

    • URL

      https://kazuhide-asakawa.com/

    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 融合タンパク質及びその利用特許権2018

    • Inventor(s)
      浅川和秀、川上浩一
    • Industrial Property Rights Holder
      情報・システム研究機構
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-186569
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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