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Therapeutic strategy for ALS with nucleic acid technology focusing on the vulnerability of TDP-43 autoregulation

Research Project

Project/Area Number 17K09751
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurology
Research InstitutionNiigata University

Principal Investigator

Sugai Akihiro  新潟大学, 脳研究所, 助教 (70758903)

Co-Investigator(Kenkyū-buntansha) 石原 智彦  新潟大学, 医歯学総合病院, 講師 (70612232)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords筋萎縮性側索硬化症 / TDP-43 / アンチセンスオリゴ / ALS
Outline of Final Research Achievements

In amyotrophic lateral sclerosis (ALS), the nuclear protein TDP-43 accumulates in the cytoplasm. TDP-43 binds to its pre-mRNA, induces alternative splicing, and autoregulates its expression levels. Here, we first constructed a mathematical model and predicted that transcriptional redundancy that underpins TDP-43 autoregulation could drive TDP-43 pathology. Then, we used an antisense oligo to suppress TDP-43 alternative splicing and manifested transcriptional redundancy. As a result, in the mouse spinal cord, the increase and fragmentation of insoluble TDP-43 and decrease in the number of motor neurons were observed. These results, which recapitulate part of the ALS pathology, suggested that this alternative splicing could be a promising therapeutic target for ALS.

Academic Significance and Societal Importance of the Research Achievements

筋萎縮性側索硬化症(ALS)は、病理学的にTDP-43の凝集と蓄積によって特徴付けられる。しかし、このTDP-43病理がどのように駆動されているのかはほとんど分かっていない。本研究は、TDP-43量調節に潜在する脆弱性に着目し、遺伝子を改変せずに、マウス脊髄において、TDP-43の病態を模倣させた。これにより、TDP-43量調節に潜在する脆弱性が、ALSの治療標的となる可能性を示した。これらの成果は、難病であるALSの治療法の開発に向けた基盤を提供する。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (12 results)

All 2020 2019 2018 2017

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 2 results) Presentation (7 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] Molecular mechanism of amyotrophic lateral sclerosis (ALS) from the viewpoint of the formation and degeneration of transactive response DNA-binding protein 43 kDa (TDP-43) inclusions2020

    • Author(s)
      Kasahara Sou、Ishihara Tomohiko、Koike Yuka、Sugai Akihiro、Onodera Osamu
    • Journal Title

      Rinsho Shinkeigaku

      Volume: 60 Issue: 2 Pages: 109-116

    • DOI

      10.5692/clinicalneurol.cn-001362

    • NAID

      130007802650

    • ISSN
      0009-918X, 1882-0654
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 増大特集 ALS2019 TDP-43封入体から解くALSの分子病態2019

    • Author(s)
      坪口 晋太朗、石原 智彦、須貝 章弘、横関 明男、小野寺 理
    • Journal Title

      BRAIN and NERVE

      Volume: 71 Issue: 11 Pages: 1183-1189

    • DOI

      10.11477/mf.1416201428

    • ISSN
      1344-8129, 1881-6096
    • Year and Date
      2019-11-01
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation2019

    • Author(s)
      Sugai Akihiro、Kato Taisuke、Koyama Akihide、Koike Yuka、Konno Takuya、Ishihara Tomohiko、Onodera Osamu
    • Journal Title

      Neurobiology of Disease

      Volume: 130 Pages: 104534-104534

    • DOI

      10.1016/j.nbd.2019.104534

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Phosphorylated TDP-43 aggregates in skeletal and cardiac muscle are a marker of myogenic degeneration in amyotrophic lateral sclerosis and various conditions.2019

    • Author(s)
      Mori F, Tada M, Kon T, Miki Y, Tanji K, Kurotaki H, Tomiyama M, Ishihara T, Onodera O, Kakita A, Wakabayashi K.
    • Journal Title

      Acta Neuropatholgica Communications

      Volume: 7 Issue: 1 Pages: 165-165

    • DOI

      10.1186/s40478-019-0824-1

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Robustness and Vulnerability of the Autoregulatory System That Maintains Nuclear TDP-43 Levels: A Trade-off Hypothesis for ALS Pathology Based on in Silico Data2018

    • Author(s)
      Sugai Akihiro、Kato Taisuke、Koyama Akihide、Koike Yuka、Kasahara Sou、Konno Takuya、Ishihara Tomohiko、Onodera Osamu
    • Journal Title

      Frontiers in Neuroscience

      Volume: 12 Pages: 0-0

    • DOI

      10.3389/fnins.2018.00028

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] TARDBP mutations distort autoregulation-relevant splicing especially under excess hnRNPA1 expression2019

    • Author(s)
      Genri Toyama, Akihiro Sugai, Yuka Koike, Akihide Koyama, Takuya Konno, Osamu Onodera
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Alteration of DNA methylation status of TARDBP 3 'UTR in sporadic ALS brain2019

    • Author(s)
      Yuka Koike, Akihiro Sugai , Akio Yokoseki, Tomohiko Ishihara, Norikazu Hara, Junko Ito Ikeuchi, Takeshi, Akiyoshi Kakita, Osamu Onodera
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] TARDBP pre-mRNA with a mutation causes disturbance of TDP-43 autoregulation via altered interaction with ALS-related splicing factors2018

    • Author(s)
      Akihiro Sugai, Takuya Konno, Akihide Koyama, Osamu Onodera
    • Organizer
      29th International Symposium on ALS/MND
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] TARDBP mutations and ALS-related splicing factors that cause disturbances in TDP-43 autoregulation2018

    • Author(s)
      Akihiro Sugai,Takuya Konno, Akihide Koyama,Osamu Onodera
    • Organizer
      第59回日本神経学会学術大会
    • Related Report
      2018 Research-status Report
  • [Presentation] A non-genetically modified iPSC-derived neuron model with an increased expression of intrinsic TDP-432017

    • Author(s)
      Akihiro Sugai, Genri Tohyama, Taisuke Kato, Tomohiko Ishihara, Osamu Onodera
    • Organizer
      Gordon Research Conferences 2017 Amyotrophic Lateral Sclerosis (ALS) & Related Motor Neuron Diseases
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] A non-genetically modified human neuronal model of ALS with an increased expression of intrinsic TDP-432017

    • Author(s)
      Akihiro Sugai, Taisuke Kato, Tomohiko Ishihara, Osamu Onodera
    • Organizer
      XXIII World Congress of Neurology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] ALS原因遺伝子TDP-43の点変異によるアレル特異的遺伝子発現の変化2017

    • Author(s)
      須貝 章弘, 廣川 祥子, 小山 哲秀, 今野 卓哉, 小野寺 理
    • Organizer
      2017年度命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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