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Pathogenesis of TDP-43 proteinopathy based on the transport defect of target mRNA

Research Project

Project/Area Number 25461302
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurology
Research InstitutionNational Center of Neurology and Psychiatry

Principal Investigator

Nagano Seiichi  国立研究開発法人国立精神・神経医療研究センター, 神経研究所疾病研究第五部, 室長 (40362727)

Co-Investigator(Renkei-kenkyūsha) NAGAI Yoshitaka  大阪大学, 大学院医学系研究科神経難病認知症探索治療学寄附講座, 教授 (60335354)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsTDP-43 / mRNA / 神経突起輸送 / 筋萎縮性側索硬化症 / 前頭側頭葉変性症
Outline of Final Research Achievements

Abnormal deposition of an RNA-binding protein TDP-43 is a hallmark in neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-U). We hypothesized that mRNA transport to neurites by TDP-43 is disturbed by deposition of the protein and failure of a specific mRNA transport is associated with ALS/FTLD-U pathogenesis, and identified mRNA of ribosomal proteins (Rp) as targets for TDP-43-mediated transport. We have proven in this study that Rp mRNA binds TDP-43 through its untranslated region and co-localizes with the protein in neurites. Down-regulation of TDP-43 expression disrupted neuritic extension and local ribosomal function. Moreover, exogenously introduced Rp was assembled into endogenous ribosomes.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (16 results)

All 2016 2015 2014 2013 Other

All Journal Article (1 results) (of which Peer Reviewed: 1 results) Presentation (12 results) (of which Invited: 3 results) Book (1 results) Remarks (2 results)

  • [Journal Article] A cysteine residue affects the conformational state and neuronal toxicity of mutant SOD1 in mice: relevance to the pathogenesis of ALS2015

    • Author(s)
      Nagano S, Takahashi Y, Yamamoto K, Masutani H, Fujiwara N, Urushitani M, Araki T
    • Journal Title

      Hum Mol Genet.

      Volume: 0n line Issue: 12 Pages: 1-13

    • DOI

      10.1093/hmg/ddv093

    • Related Report
      2015 Annual Research Report 2014 Research-status Report
    • Peer Reviewed
  • [Presentation] TDP-43 transports mRNA of ribosomal proteins2015

    • Author(s)
      Nagano S, Hirokawa S, Nishizawa M, Sakimura K, Onodera O, Araki T.
    • Organizer
      第38回日本分子生物学会年会、第88回日本生化学会大会合同大会
    • Place of Presentation
      神戸ポートアイランド、神戸
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] 銅を介した変異SOD1の運動神経毒性はシステイン残基に依存する2015

    • Author(s)
      長野清一、高橋陽子、山本和弘、増谷 弘、藤原範子、漆谷 真、荒木敏之.
    • Organizer
      メタルバイオサイエンス研究会2015
    • Place of Presentation
      名古屋国際センター、名古屋
    • Year and Date
      2015-08-27
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Role of cysteine residue of mutant SOD1 in the pathogenesis of ALS2015

    • Author(s)
      Nagano S, Takahashi Y, Yamamoto K, Masutani H, Fujiwara N, Urushitani M, Araki T.
    • Organizer
      第38回日本神経科学大会
    • Place of Presentation
      神戸国際会議場・神戸国際展示場、神戸
    • Year and Date
      2015-07-28
    • Related Report
      2015 Annual Research Report
  • [Presentation] TDP-43 transports mRNA of ribosomal proteins2015

    • Author(s)
      Nagano S, Hirokawa S, Nishizawa M, Sakimura K, Onodera O, Araki T.
    • Organizer
      第56回日本神経学会学術大会
    • Place of Presentation
      新潟コンベンションセンター、新潟
    • Year and Date
      2015-05-20
    • Related Report
      2015 Annual Research Report
  • [Presentation] Role of cysteine residue of mutant SOD1 in the pathogenesis of ALS2014

    • Author(s)
      Nagano S, Yamamoto K, Urushitani M, Fujiwara N, Araki T
    • Organizer
      25th International Symposium on ALS/MND
    • Place of Presentation
      Square Brussels Meeting Centre, Brussels, Belgium
    • Year and Date
      2014-12-05 – 2014-12-07
    • Related Report
      2014 Research-status Report
  • [Presentation] Identification of target mRNA transported to axons by TDP-432014

    • Author(s)
      Seiichi Nagano, Toshiyuki Araki
    • Organizer
      国立精神・神経医療研究センター―マックスプランク合同シンポジウム
    • Place of Presentation
      ザ・プリンス箱根、箱根
    • Year and Date
      2014-11-05 – 2014-11-07
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] Identification of target mRNA transported to axons by TDP-432014

    • Author(s)
      Seiichi Nagano, Sachiko Hirokawa, Masatoyo Nishizawa, Kenji Sakimura, Osamu Onodera, Toshiyuki Araki
    • Organizer
      第37回日本神経科学大会
    • Place of Presentation
      パシフィコ横浜、横浜
    • Year and Date
      2014-09-11 – 2014-09-13
    • Related Report
      2014 Research-status Report
  • [Presentation] 変異型SOD1の運動神経毒性におけるシステイン残基の役割2014

    • Author(s)
      長野清一、山本和弘、漆谷 真、荒木敏之
    • Organizer
      第55回日本神経学会学術大会
    • Place of Presentation
      福岡国際会議場・福岡サンパレス・福岡国際センター、福岡
    • Year and Date
      2014-05-21 – 2014-05-24
    • Related Report
      2014 Research-status Report
  • [Presentation] TDP-43による翻訳関連遺伝子mRNAの神経突起への輸送2013

    • Author(s)
      長野清一、荒木敏之
    • Organizer
      第54回日本神経学会学術大会
    • Place of Presentation
      東京国際フォーラム、東京
    • Related Report
      2013 Research-status Report
  • [Presentation] Identification of mRNA targeted to axons by TDP-432013

    • Author(s)
      S. Nagano
    • Organizer
      新潟脳神経研究会特別例会
    • Place of Presentation
      新潟大学脳研究所、新潟
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] Identification of mRNA transported to axons by TDP-432013

    • Author(s)
      S. Nagano, T. Araki
    • Organizer
      第4回新潟大学脳研究所共同研究拠点国際シンポジウム
    • Place of Presentation
      新潟大学脳研究所、新潟
    • Related Report
      2013 Research-status Report
  • [Presentation] TDP-43による翻訳関連遺伝子mRNAの神経突起への輸送2013

    • Author(s)
      長野清一、荒木敏之
    • Organizer
      第32回日本認知症学会学術集会
    • Place of Presentation
      キッセイ文化ホール、松本
    • Related Report
      2013 Research-status Report
  • [Book] Novel Aspects of Amyotrophic Lateral Sclerosis2016

    • Author(s)
      Nagano S, Araki T.
    • Publisher
      InTech
    • Related Report
      2015 Annual Research Report
  • [Remarks] 所属研究部ホームページ

    • URL

      http://www.ncnp.go.jp/nin/guide/r5/member/s-nagano.html

    • Related Report
      2015 Annual Research Report 2014 Research-status Report
  • [Remarks] 所属研究部ホームページ

    • URL

      http://www.ncnp.go.jp/nin/guide/r5/member/s-nagano.html

    • Related Report
      2013 Research-status Report

URL: 

Published: 2014-07-25   Modified: 2019-07-29  

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