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Function of chromatin remodelers in nuclear compartment organization of Cabeza and ALS pathogenesis

Research Project

Project/Area Number 15F15789
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section外国
Research Field Genetics/Chromosome dynamics
Research InstitutionKyoto Institute of Technology

Principal Investigator

山口 政光  京都工芸繊維大学, 応用生物学系, 教授 (00182460)

Co-Investigator(Kenkyū-buntansha) LO PICCOLO LUCA  京都工芸繊維大学, 応用生物学系, 外国人特別研究員
Project Period (FY) 2015-11-09 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2017: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2016: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2015: ¥800,000 (Direct Cost: ¥800,000)
Keywords筋萎縮性側索硬化症 / FUS / ショウジョウバエ / lncRNA / LAMP1 / 神経変性疾患 / ALS / hsrω / Cabeza / 細胞内局在 / シナプス / hnRNP / long non-coding RNA
Outline of Annual Research Achievements

前年度までに、ショウジョウバエのlncRNAの一つであるhsrωがヒトALSの原因遺伝子FUSのショウジョウバエホモログdFUSに遺伝学的にまた物理的に相互作用することを明らかにした。またhsrωのノックダウン系統を用いた解析から、hsrωがdFUS mRNAレベルを制御すると共に、dFUSタンパク質の核・細胞質局在のバランスを調節することを明らかにした。平成29年度は、それまでの研究を発展させて、遺伝学実験と生化学的解析を組み合わせることにより、ヒトFUSをショウジョウバエの複眼原基で発現させると、ヒトFUSは可溶性分画に存在し、その結果細胞毒性を示して、赤色色素の消失を伴う成虫複眼形態異常を誘導することを明らかにした。このショウジョウバエでhsrω lncRNAをノックダウンすると、この複眼形態異常がレスキューされることを見出した。hsrωノックダウンにより、dFUS mRNAレベルが低下した。また面白いことに、hsrωノックダウンが可溶性のヒトFUSを減少させ、またそれと同時に不溶性のヒトFUS-LAMP1凝集体形成を促進することを見出した。hsrωノックダウンによりもたらされるこれらの現象が、結果的に細胞毒性を示す可溶性のヒトFUS量を減少させ、複眼形態異常をレスキューしたと考えられる。さらに詳細な解析を進めることにより、細胞質のFUS-LAMP1凝集体は、プロテアソーム、オートファジー、リソソームのいずれによる分解も受けず、細胞質内の安全な貯蔵物として隔離されて存在することを見出した。この発見は細胞質のFUS凝集体形成へのLAMP1の新しい機能を示したものとして学術的意義がある。またこれらの研究は、FUSタンパク質の異常が関与する様々な神経変性疾患の理解に役立つと共に、ALSやFTLDなどの新規治療標的候補を提示したものとしても意義がある。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Report

(3 results)
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (16 results)

All 2018 2017 2016 2015 Other

All Int'l Joint Research (1 results) Journal Article (5 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 5 results,  Acknowledgement Compliant: 1 results,  Open Access: 2 results) Presentation (8 results) (of which Int'l Joint Research: 5 results) Book (1 results) Remarks (1 results)

  • [Int'l Joint Research] University of Chiang Mai(Thailand)

    • Related Report
      2016 Annual Research Report
  • [Journal Article] A new Drosophila model of Ubiquilin knockdown shows the effect of impaired proteostasis on locomotive and learning abilities.2018

    • Author(s)
      Jantrapirom S, Lo Piccolo L, Yoshida H, Yamaguchi M.
    • Journal Title

      Exp Cell Res.

      Volume: 362 Issue: 2 Pages: 4611-471

    • DOI

      10.1016/j.yexcr.2017.12.010

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] RNAi of arcRNA hsrω Affects Sub- Cellular Localization of Drosophila FUS to Drive Neurodiseases.2017

    • Author(s)
      Luca Lo Piccolo and Masamitsu Yamaguchi
    • Journal Title

      Exp. Neurol.

      Volume: 292 Pages: 125-134

    • DOI

      10.1016/j.expneurol.2017.03.011

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] FUS toxicity is rescued by the modulation of lncRNA hsrω expression in Drosophila melanogaster.2017

    • Author(s)
      Piccolo, L. L., Jantrapirom, S., Nagai, Y. and Yamaguchi M.
    • Journal Title

      Sci. Rep.

      Volume: 7(1) Issue: 1 Pages: 15660-15660

    • DOI

      10.1038/s41598-017-15944-y

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ISWI ATP-dependent remodeling of nucleoplasmic omega speckles in the brain of Drosophila melanogaster2017

    • Author(s)
      Luca Lo Piccolo, Andrea Attardi, Rosa Bonaccorso, Lorenzo Li Greci, Giorgio Giurato, Antonia Maria Rita Ingrassia and Maria Cristina Onorati
    • Journal Title

      J. Genet. Genomics

      Volume: 44 Issue: 2 Pages: 85-94

    • DOI

      10.1016/j.jgg.2016.12.002

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Nuclear and Cytoplasmic Soluble Proteins Extraction from a Small Quantity of Drosophila's Whole Larvae and Tissues.2015

    • Author(s)
      Lo Piccolo, Bonaccorso R, Onorati MC
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 16 Issue: 6 Pages: 12360-12367

    • DOI

      10.3390/ijms160612360

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] RNAi for the large non-coding hsrω transcripts shows severe defects in locomotion and short life span2016

    • Author(s)
      Luca Lo Piccolo
    • Organizer
      37th Annual Meeting of the Molecular Biology Society of Japan
    • Place of Presentation
      Yokohama, Japan
    • Year and Date
      2016-12-10
    • Related Report
      2016 Annual Research Report
  • [Presentation] A new Drosophila melanogaster model reveals the role of the lncrna hsrω in ALS2016

    • Author(s)
      Luca Lo Piccolo
    • Organizer
      Seminar on Asia Insect and Biomedical Research 2016
    • Place of Presentation
      Chiang Mai, Thailand
    • Year and Date
      2016-09-07
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The role of ω-speckles nuclear body in diseases affecting central nervous system2016

    • Author(s)
      Luca Lo Piccolo
    • Organizer
      Symposium in 68th Annual Meeting of the Japan Society of Cell Biology
    • Place of Presentation
      Kyoto, Japan
    • Year and Date
      2016-06-15
    • Related Report
      2016 Annual Research Report
  • [Presentation] The role of ω-speckles nuclear body in diseases affecting central nervous system2016

    • Author(s)
      Luca Lo Piccolo
    • Organizer
      68th Annual Meeting of the japan society of cell biology
    • Place of Presentation
      京都テルサ(京都府京都市)
    • Year and Date
      2016-06-15
    • Related Report
      2015 Annual Research Report
  • [Presentation] RNAi for the large non coding hsrω transcripts suppresses neurodegenerative pathogenesis Cabeza-related in Drosophila models2016

    • Author(s)
      Luca Lo Piccolo and Masamitsu Yamaguchi
    • Organizer
      EMBL The Epitranscriptome Conference
    • Place of Presentation
      Heidelberg, Germany
    • Year and Date
      2016-04-20
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] RNAi for the large non coding hsrω transcripts suppresses neurodegenerative pathogenesis Cabeza-related in Drosophila models2016

    • Author(s)
      Luca Lo Piccolo and Masamitsu Yamaguchi
    • Organizer
      EMBL The Epitranscriptome Conference
    • Place of Presentation
      ハイデルベルグ(ドイツ)
    • Year and Date
      2016-04-20
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Chromatin remodeler, lncRNA and hnRNPs: new insights into the development of the central nervous system of Drosophila2015

    • Author(s)
      Luca Lo Piccolo and Cristina Onorati
    • Organizer
      EMBO/EMBL Symposium
    • Place of Presentation
      ハイデルベルグ(ドイツ)
    • Year and Date
      2015-06-14
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Modulation of ω-speckles structure by ISWI chromatin remodeler: new insights into neurogenesis of Drosophila melanogaster2015

    • Author(s)
      Luca Lo Piccolo
    • Organizer
      12th International Conference on Drosophila Heterochromatin
    • Place of Presentation
      パレルモ(イタリア)
    • Year and Date
      2015-05-24
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Book] Drosophila Models for Human Diseases (Masamitsu Yamaguchi ed.)2018

    • Author(s)
      Piccolo, L. L.
    • Publisher
      Springer
    • ISBN
      9789811305283
    • Related Report
      2017 Annual Research Report
  • [Remarks] 染色体工学研究室ホームページ

    • URL

      http://www.bio.kit.ac.jp/chromosome/INDEX.html

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report

URL: 

Published: 2015-11-26   Modified: 2024-03-26  

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