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exploration of CRAG gene therapy for neurodegenerative diseases

Research Project

Project/Area Number 25460074
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Biological pharmacy
Research InstitutionTokyo University of Pharmacy and Life Science

Principal Investigator

Inatome Ryoko  東京薬科大学, 生命科学部, 研究員 (90408691)

Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords神経変性疾患 / SRF / CRAG / 脊髄小脳変性症 / ALS / 遺伝子治療
Outline of Final Research Achievements

We previously demonstrated that CRAG facilitated the degradation of expanded polyglutamine protein via the nuclear ubiquitin-proteasome pathway and suggested that targeted delivery of CRAG may be useful as a gene therapy for neurodegenerative diseases such as polyglutamine diseases. However, the physiological relevance of CRAG in vivo is unknown. Here, we analyzed CRAG KO mice. Both whole-body and neuron-specific CRAG KO mice spontaneously developed severe neurodegenerative phenotypes cell death and lethality, within 1 month of birth. Kainic acid–induced c-fos expression was intensively suppressed in the hippocampus in these KO mice. Furthermore, CRAG interacted with ELK1, a coactivator of SRF, leading to ELK1-dependent SRF-c-fos induction. We conclude that CRAG plays a critical role in neuronal development and survival, at least in part through ELK1-dependent SRF-c-fos activation, and therefore suggesting the usefulness of CRAG gene therapy for neurodegenerative diseases.

Report

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

    (5 results)

All 2015 2014 2013 Other

All Journal Article (2 results) (of which Peer Reviewed: 2 results) Presentation (3 results)

  • [Journal Article] Roles of mitochondrial ubiquitin ligase MITOL/MARCH5 in mitochondrial dynamics and diseases2014

    • Author(s)
      Nagashima, S., Tokuyama, T., Yonashiro, R., Inatome, R., and Yanagi S.
    • Journal Title

      J. Biochem

      Volume: 155 Issue: 5 Pages: 273-279

    • DOI

      10.1093/jb/mvu016

    • Related Report
      2014 Research-status Report 2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2.2013

    • Author(s)
      Sugiura, A., Nagashima, S., Tokuyama, T., Amo, T., Matsuki, Y., Ishido, S., Kudo, Y., McBride, H.M., Fukuda, T., Matsushita, T., Inatome, R., and C Yanagi, S.
    • Journal Title

      Mol. Cell

      Volume: 51 Issue: 1 Pages: 1-15

    • DOI

      10.1016/j.molcel.2013.04.023

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] CRAGによって形成されるMitoTracker陽性の核内封入体の解析2015

    • Author(s)
      玉井 勇、長島 駿、福田敏史、稲留涼子、柳 茂
    • Organizer
      BMB 2015第88回日本生化学会大会合同大会・第38回日本分子生物学会年会
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-03
    • Related Report
      2015 Annual Research Report
  • [Presentation] 神経回路形成関連分子CRAGによる生存シグナルと神経変性疾患への応用2014

    • Author(s)
      長島 駿、稲留涼子、柳 茂
    • Organizer
      第87回日本生化学会大会
    • Place of Presentation
      京都
    • Year and Date
      2014-10-18
    • Related Report
      2014 Research-status Report
  • [Presentation] Role of mitochondrial ubiquitin ligase MITOL in mitochondrial dynamics and diseases

    • Author(s)
      長島 駿, 杉浦 歩, 徳山剛士, 武田啓佑, 稲留涼子, 柳 茂
    • Organizer
      第86回日本生化学会大会
    • Place of Presentation
      横浜
    • Related Report
      2013 Research-status Report

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

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