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Regulation of neural circuit by Fragile X Mental Retardation Protein - its relation to ubiquitination and local translation

Research Project

Project/Area Number 16K07061
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionYokohama City University

Principal Investigator

Yukio Sasaki  横浜市立大学, 生命医科学研究科, 准教授 (10295511)

Research Collaborator Ito Hidenori  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords横浜市 / 神経生物学 / 脆弱X症候群 / ユビキチン / セマフォリン
Outline of Final Research Achievements

The role of fragile X mental retardation protein (FMRP) in axon guidance and synapse formation during neural circuit formation was examined in relation to ubiquitination and local translation. Our results suggest that after stimulation with the axon guidance molecule Sema3A, FMRP was degraded in growth cones by the ubiquitin-proteasome system, followed by that local translation was triggered to induce a morphological change of growth cones. We also identified the ubiquitination related gene for FMRP, and found that the gene product induced disappearance of FMRP after granular accumulation of FMRP. FMRP-containing granules were also observed during synapse formation. Therefore, our findings suggested that ubiquitination of FMRP is involved in neural circuit formation through regulation of granule formation and local translation of FMRP.

Academic Significance and Societal Importance of the Research Achievements

脆弱X症候群 (FXS)は遺伝性の発達障害としては最も頻度の高い疾患であり、知的障害、自閉症等の症状を示す。FXSの原因遺伝子産物であるFMRPは神経細胞において軸索、樹状突起における局所翻訳を制御し神経回路形成において重要な役割を担っているが、そのメカニズムは不明であった。我々が今回明らかにしたメカニズムは神経回路の発達にFMRPのユビキチン化が関与することを示唆する結果である。FXSに対する創薬は自閉症全般に応用できると考えられ、多くの製薬会社が参入しているが、まだ有効な薬剤は開発されていない。本研究の親展によりFXSの病態の一端が明らかになり、治療法の開発や創薬に結びつく可能性がある。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (9 results)

All 2018 2017 2016

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (7 results)

  • [Journal Article] Fragile X mental retardation protein regulates accumulation of the active zone protein Munc18-1 in presynapses via local translation in axons during synaptogenesis.2018

    • Author(s)
      Parvin S, Takeda R, Sugiura Y, Neyazaki M, Nogi T, Sasaki Y.
    • Journal Title

      Neurosci Res.

      Volume: S0168-0102 Pages: 30431-0

    • DOI

      10.1016/j.neures.2018.09.013

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulation of dendritic development by Semaphorin 3A through novel intracellular remote signaling2016

    • Author(s)
      Goshima Y, Yamashita N, Nakamura F, Sasaki Y
    • Journal Title

      Cell Adh Migr

      Volume: 10 Issue: 6 Pages: 627-640

    • DOI

      10.1080/19336918.2016.1210758

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 人工誘導プレシナプスを用いた神経活動計測系の開発2017

    • Author(s)
      武田怜之雅、Shumaia Parvin、佐々木幸生
    • Organizer
      第136回日本薬理学会関東部会
    • Related Report
      2017 Research-status Report
  • [Presentation] Fragile X mental retardation protein regulates accumulation of the active zone protein Munc18 in presynapses via local translation.2017

    • Author(s)
      Shumaia Parvin, Renoma Takeda, Shino Endo, Yu Sugiura, Yukio Sasaki
    • Organizer
      第40回神経科学学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 脆弱X精神遅滞タンパク質によるシナプス前終末の形成と機能の制御2017

    • Author(s)
      佐々木幸生、Shumaia Parvin、武田怜之雅
    • Organizer
      第39回神経組織培養研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] マイクロRNA382のエクソソームを介した分泌機構と標的遺伝子の解析2017

    • Author(s)
      木村貴洋、田中智美、佐々木幸生
    • Organizer
      第137回日本薬理学会関東部会
    • Related Report
      2017 Research-status Report
  • [Presentation] 大脳皮質神経細胞培養系において脱分極刺激により特定のマイクロRNAがエクソソーム中に増加する2016

    • Author(s)
      田中 智美、高橋 徹、佐々木 幸生
    • Organizer
      第134回日本薬理学会関東部会
    • Place of Presentation
      国際医療福祉大学(栃木県大田原市)
    • Related Report
      2016 Research-status Report
  • [Presentation] 脆弱X精神遅滞タンパク質の分解と神経回路形成2016

    • Author(s)
      佐々木 幸生、高畠 将
    • Organizer
      第38回神経組織培養研究会
    • Place of Presentation
      横浜ランドマークタワー(神奈川県横浜市)
    • Related Report
      2016 Research-status Report
  • [Presentation] 脆弱X精神遅滞タンパク質に対するユビキチンリガーゼの同定の試み2016

    • Author(s)
      高畠 将、高橋 徹、梁 明秀、五嶋 良郎、佐々木 幸生
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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