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Pathological and therapeutic research of sporadic ALS

Research Project

Project/Area Number 17K08077
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Veterinary medical science
Research InstitutionShiga University of Medical Science

Principal Investigator

Morimura Toshifumi  滋賀医科大学, 神経難病研究センター, 助教 (20333338)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
KeywordsTDP-43 / ALS / ノックダウン / 細胞質凝集体 / SOD1 / VHL / CTF-25 / 不溶性蛋白質 / S409/S410リン酸化 / ユビキチン / プロテアソーム / オートファジー / 小胞体ストレス
Outline of Final Research Achievements

Cytoplasmic mis-aggregation and nuclear-loss of TAR DNA binding protein of 43KDa (TDP-43) are observed in the lesions of sporadic amyotrophic lateral sclerosis (ALS). To understand a mechanism how nuclear-loss of TDP-43 involves in the pathogenesis of sporadic ALS, transcriptome analysis was performed. I found a gene whose transcript and translation products are drastically reduced in the TDP-43 silenced HeLa and HEK293A cells. The gene product preferentially associated with aggregated TDP-43 species and superoxide dismutase (SOD1) mutants with mutations related to familial ALS, and it was also co-precipitated with von Hipple-Lindau (VHL), a substrates recognition unit of Cullin-2 E3 ligase complex, which had been identified as an E3 of C-terminal truncated TDP-43 and ALS associated SOD1 mutants. These results suggest that the TDP-43 deficiency may associate with clearance of misfolded TDP-43 and SOD1 through regulating VHL.

Academic Significance and Societal Importance of the Research Achievements

孤発性ALSは、 原因蛋白質であるTDP-43の凝集塊形成による蛋白質毒性とその機能不全により引き起こされるものと考えられている。本研究期間に、TDP-43により発現制御を受ける遺伝子産物の一つが、高凝集性TDP-43や家族性ALSの原因蛋白質による凝集塊に共局在し、これら異常蛋白質の除去に関与している可能性を見出した。即ち、異常蛋白質からの毒性とTDP-43の機能不全はそれぞれ異なる分子メカニズムによりALSの病理基盤を形成すると考えられてきたが、本研究により共通のプレイヤーが存在する可能性が示唆された。

Report

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

    (7 results)

All 2020 2019 2018 2017

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (5 results)

  • [Journal Article] Generation of transgenic cynomolgus monkeys overexpressing the gene for amyloid-β precursor protein2020

    • Author(s)
      Seita Y, Morimura T, Watanabe N, Iwatani C, Tsuchiya H, Nakamura S, Suzuki T, Yanagisawa D, Tsukiyama T, Nakaya M, Okamura E, Muto M, Ema M, Nishimura M, Tooyama I.
    • Journal Title

      Journal of Alzheimer's Disease

      Volume: - Issue: 1 Pages: 45-60

    • DOI

      10.3233/jad-191081

    • NAID

      120006859791

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Elimination of TDP-43 inclusions linked to amyotrophic lateral sclerosis by a misfolding-specific intrabody with dual proteolytic signals.2018

    • Author(s)
      Tamaki Y, Shodai A, Morimura T, Hikiami R, Minamiyama S, Ayaki T, Tooyama I, Furukawa Y, Takahashi R, Urushitani M.
    • Journal Title

      Scientific Reports

      Volume: 印刷中 Issue: 1 Pages: 6030-6030

    • DOI

      10.1038/s41598-018-24463-3

    • NAID

      120006482849

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] アルツハイマー病関連変異型amyloid precursor protein発現トランスジェニックカニクイザルの作出2019

    • Author(s)
      守村 敏史、清田 弥寿成、渡邊 直希 、岩谷 千鶴、土屋 英明、 中村 紳一郎、鈴木 利治, 依馬 正次, 西村 正樹, 遠山 育夫
    • Organizer
      第46回日本脳科学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Generating new ALS model mice replicating TDP-43 proteinopathy.2018

    • Author(s)
      引網 亮太、小代 明美、南山 素三雄、玉木 良高、守村 敏史、高橋 良輔、漆谷 真
    • Organizer
      第59回日本神経学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] In vivo interaction between GTP cyclohydrolase 1 and its regulatory protein GFRP2018

    • Author(s)
      Jean-Pierre Bellier, Toshifumi Morimura, Yu Xie, Ikuo Tooyama
    • Organizer
      第61回日本神経化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] Degradative intrabody for selective elimination of pathogenic TDP-43 aggregates in vitro and in murine embryos' cerebrum.2017

    • Author(s)
      Tamaki Y, Shodai A, Hikiami R, Minamiyama S, Morimura T, Ayaki T, Takahashi R, Urushitani M.
    • Organizer
      World Congress of Neurology
    • Related Report
      2017 Research-status Report
  • [Presentation] Development of an effective technology for inductive differentiation from bone marrow-derived mononuclear cells to neuroprotective microglia.2017

    • Author(s)
      Kobashi S, Terashima T, Nakae Y, Katagi M , Morimura T, Kojima H, Urushitani M.
    • Organizer
      World Congress of Neurology
    • Related Report
      2017 Research-status Report

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

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