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The biological significance of the cleavage of ALS-associated protein TDP-43

Research Project

Project/Area Number 25670419
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Neurology
Research InstitutionOsaka University

Principal Investigator

KAWAHARA Yukio  大阪大学, 医学(系)研究科(研究院), 教授 (80542563)

Project Period (FY) 2013-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords脳神経疾患 / 筋萎縮性側索硬化症 / 痴呆 / カスパーゼ / 細胞死 / 前頭側頭葉変性症 / ネクローシス / アポトーシス / 遺伝子
Outline of Final Research Achievements

TDP-43 and its C-terminal fragment of 25 kDa (CTF25) play critical roles in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although overexpression of TDP-43 in cultured cells and animals results in the production of CTF25, the cleavage site that generates CTF25 and biological significance of the cleavage remain undetermined. In this study, we identify Asp174 as a predominant cleavage site for CTF25. TDP-43 is cleaved initially after Asp174, which activates caspase-3/7 to accelerate TDP-43 fragmentation. Consequently, blockage of this cleavage results in a severe delay in TDP-43 clearance and prolonged necrotic cell death. We further show that endoplasmic reticulum membrane-bound caspase-4 is the enzyme responsible for the cleavage after Asp174 and inhibition of caspase-4 activity slows TDP-43 fragmentation and reduces cell viability. These findings suggest that caspase-4-mediated cleavage after Asp174 is an initiator of TDP-43 clearance.

Report

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

    (18 results)

All 2015 2014 2013 Other

All Journal Article (11 results) (of which Peer Reviewed: 5 results,  Acknowledgement Compliant: 2 results,  Open Access: 1 results) Presentation (5 results) (of which Invited: 2 results) Remarks (2 results)

  • [Journal Article] The cleavage pattern of TDP-43 determines its rate of clearance and cytotoxicity.2015

    • Author(s)
      Li, Q., Yokoshi, M., Okada, H., Kawahara, Y.
    • Journal Title

      Nature Communications

      Volume: 6 Issue: 1 Pages: 6183-6183

    • DOI

      10.1038/ncomms7183

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Cross-Linking and Immunopresipitation of Nuclear RNA-Binding Proteins2015

    • Author(s)
      Li,Q., Uemura,Y., Kawahara,Y.
    • Journal Title

      Methods in Molecular Biology

      Volume: 1262 Pages: 247-263

    • DOI

      10.1007/978-1-4939-2253-6_15

    • ISBN
      9781493922529, 9781493922536
    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] RNA代謝異常を介した神経変性疾患の発症病態2015

    • Author(s)
      余越萌, 河原行郎
    • Journal Title

      ファルマシア

      Volume: 51(1) Pages: 37-41

    • NAID

      130007447862

    • Related Report
      2014 Annual Research Report
  • [Journal Article] Direct binding of Ataxin-2 to distinct elements in 3' UTRs promotes mRNA stability and protein expression.2014

    • Author(s)
      Yokoshi, M., Li, Q., Yamamoto, M., Okada, H., Suzuki, Y., and Kawahara, Y.
    • Journal Title

      Molecular cell

      Volume: 55 Issue: 2 Pages: 186-198

    • DOI

      10.1016/j.molcel.2014.05.022

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 神経変性疾患関連タンパク質Ataxin-2は3’非翻訳領域にある特定の配列に直接結合することによって、mRNAの安定性を促進しタンパク質発現を増加させる2014

    • Author(s)
      余越萌, 河原行郎
    • Journal Title

      新着論文レビュー

      Volume: e9044

    • Related Report
      2014 Annual Research Report
    • Open Access
  • [Journal Article] RNA代謝と神経変性2014

    • Author(s)
      植村有里, 河原行郎
    • Journal Title

      Brain Medical

      Volume: 26(3) Pages: 209-215

    • Related Report
      2014 Annual Research Report
  • [Journal Article] RNA疾患研究の新展開2014

    • Author(s)
      河原行郎, 塩見美喜子
    • Journal Title

      Medical Science Digest

      Volume: 40(7) Pages: 324-325

    • Related Report
      2014 Annual Research Report
  • [Journal Article] Human diseases caused by germline and somatic abnormalities in microRNA and microRNA-related genes.2014

    • Author(s)
      Kawahara, Y
    • Journal Title

      Congenital Anomalies

      Volume: 54 Issue: 1 Pages: 12-21

    • DOI

      10.1111/cga.12043

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] ノンコーディングRNAと神経変性疾患2013

    • Author(s)
      河原 行郎
    • Journal Title

      医学のあゆみ

      Volume: 247 Pages: 421-426

    • Related Report
      2013 Research-status Report
  • [Journal Article] 筋萎縮性側索硬化症とRNA結合タンパク質2013

    • Author(s)
      河原 行郎
    • Journal Title

      領域融合レビュー

      Volume: e010 Pages: 1-8

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] microRNAの修飾とその機能2013

    • Author(s)
      余越 萌、河原 行郎
    • Journal Title

      実験医学(増刊)

      Volume: 31 Pages: 1124-1131

    • Related Report
      2013 Research-status Report
  • [Presentation] 神経変性疾患に関連するTDP-43の断片化機構とその生理的意義について2014

    • Author(s)
      河原 行郎
    • Organizer
      第5回神経科学と構造生物学の融合研究会
    • Place of Presentation
      吹田 大阪
    • Year and Date
      2014-12-04 – 2014-12-05
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] TDP-43断片化の生理的意義について2014

    • Author(s)
      河原 行郎
    • Organizer
      第55回日本神経学会学術大会
    • Place of Presentation
      博多 福岡
    • Year and Date
      2014-05-24
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Identification of common targets of TDP-43 and FUS by PAR-CLIP.2014

    • Author(s)
      1. Li, Q., Yamamoto, M., Yokoshi, M., Suzuki, Y., Kawahara Y.,
    • Organizer
      New Frontier of Molecular Neruopathology 2014
    • Place of Presentation
      東京
    • Related Report
      2013 Research-status Report
  • [Presentation] PAR-CLIP法を用いたTDP-43とFUSに共通するターゲットの同定2013

    • Author(s)
      山本 宗隆、李 全、鈴木 穣、河原 行郎
    • Organizer
      第15回RNAミーティング
    • Place of Presentation
      愛媛
    • Related Report
      2013 Research-status Report
  • [Presentation] Comprehensive analysis of the roles of TDP-43 and FUS in RNA processing2013

    • Author(s)
      Li, Q., Yamamoto, M., Seno, S., Matsuda, H., Suzuki, Y., Kawahara Y
    • Organizer
      第36回日本神経科学大会
    • Place of Presentation
      京都
    • Related Report
      2013 Research-status Report
  • [Remarks] ALS等で蓄積するタンパク質の分解メカニズムを解明

    • URL

      http://resou.osaka-u.ac.jp/ja/research/2015/20150129_1

    • Related Report
      2014 Annual Research Report
  • [Remarks] 大阪大学大学院医学系研究科遺伝子機能制御学教室研究成果

    • URL

      http://www.med.osaka-u.ac.jp/pub/rna/publications.html

    • Related Report
      2013 Research-status Report

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

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