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Identification of splicing factors that bind to expanded GGGGCC repeat and TDP-43 mRNA

Research Project

Project/Area Number 25670417
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Neurology
Research InstitutionNiigata University

Principal Investigator

Onodera Osamu  新潟大学, 脳研究所, 教授 (20303167)

Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords筋萎縮性側索硬化症 / 神経病態 / RNA代謝 / RNA結合蛋白
Outline of Final Research Achievements

Expansion of a GGGGCC (G4C2) repeat in the first intron of C9ORF72 is the most common cause of familial frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTLD/ALS). TAR DNA-binding protein 43 (TDP-43), encoded by TARDBP, is a major component of neuronal cytoplasmic inclusions, which are observed in affected neurons in patients with ALS. TDP-43 pathology is also observed in patients with the G4C2 repeat expansion. We have hypothesized that the repeat expansion might cause dysregulation of the alternative splicing of TDP-43 mRNA. We generated (G4C2)9 repeats as a normal control or (G4C2)82 repeats expression vectors and identified binding proteins. We transfected these RBPs siRNA into HEK293T cells and analyzed the TDP-43 alternative splicing. We performed in-situ hybridization and immunofluorescent double staining analysis using HEK293T cells. We found two G4C2 binding RBPs. However, we could not observe these proteins co-localized with (G4C2)82 repeats foci.

Report

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

    (13 results)

All 2015 2014 2013

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (9 results) (of which Int'l Joint Research: 4 results,  Invited: 2 results)

  • [Journal Article] C9ORF72 repeat-associated non-ATG-translated polypeptides are distributed independently of TDP-43 in a Japanese patient with c9ALS2014

    • Author(s)
      Konno T ほか
    • Journal Title

      Neuropathol Appl Neurobiol

      Volume: 40 Issue: 6 Pages: 783-788

    • DOI

      10.1111/nan.12157

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories.2014

    • Author(s)
      AkimotoC, Onodera O ら
    • Journal Title

      J Med Genet.

      Volume: 51 Issue: 6 Pages: 419-424

    • DOI

      10.1136/jmedgenet-2014-102360

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] Bunina bodies in motor and non-motor neurons revisited: A pathological study of an ALS patient after long-term survival on a respirator.2014

    • Author(s)
      Kimura T, Jiang H, Konno T, Seto M, Iwanaga K, Tsujihata M, Satoh A, Onodera O, Kakita A, Takahashi H.
    • Journal Title

      Neuropathology

      Volume: なし Issue: 4 Pages: 392-397

    • DOI

      10.1111/neup.12105

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Japanese amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72.2013

    • Author(s)
      Konno T
    • Journal Title

      J Neurol Neurosurg Psychiatry

      Volume: 84(4) Issue: 4 Pages: 398-401

    • DOI

      10.1136/jnnp-2012-302272

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] Depletion of TDP-43 induces mitochondrial fragmentation.2015

    • Author(s)
      Ito G, Koyama A, Shiga A, Hirokawa S, Toyoshima Y, Kakita A, Nishizawa M, Onodera O.
    • Organizer
      ALS MND 2015 26th International Symposium on ALS/MND
    • Place of Presentation
      Orland (USA)
    • Year and Date
      2015-12-11
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The SMN gene copy number states in Japanese ALS patients.2015

    • Author(s)
      T.Ishihara, S.Toyoda, A.Koyama, R.Nakamura, G. Tohnai, N.Atsuta, G.Sobue, M.Nishizawa, O. Onodera
    • Organizer
      10th Brain Research Conference: RNA Metabolism in Neurological Disease
    • Place of Presentation
      Chicago (USA)
    • Year and Date
      2015-10-15
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Detection of CRISPR/Cas9 induced-rare genome editing events by droplet-digital PCR.2015

    • Author(s)
      Siga A, Onodera O.
    • Organizer
      10th Brain Research Conference: RNA Metabolism in Neurological Disease
    • Place of Presentation
      Chicago (USA)
    • Year and Date
      2015-10-15
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Overexpression of intrinsic TDP-43 by disruption of the autoregulation in vivo.2015

    • Author(s)
      Akihiro Sugai, Taisuke Kato, Masatoyo Nishizawa, Osamu Onodera.
    • Organizer
      EMBO | EMBL Symposia Mechanisms of Neurodegeneration
    • Place of Presentation
      Heidelberg (Germany)
    • Year and Date
      2015-07-14
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Droplet digital PCR system fascilitate to clone the genome-edited iPS cells.2015

    • Author(s)
      Atsushi Shiga, Masatoyo Nishizaw, Osamu Onodera.
    • Organizer
      Molecular Med Tri-Con 2015
    • Place of Presentation
      San Francisco CA USA
    • Year and Date
      2015-02-16 – 2015-02-18
    • Related Report
      2014 Research-status Report
  • [Presentation] The reduction of minor spliceosome and aberrant splicing in ALS.2014

    • Author(s)
      T. Ishihara., A. Koyama M., Nishizawa. O. Onodera
    • Organizer
      Cell Symposium
    • Place of Presentation
      Berkeley, CA, USA
    • Year and Date
      2014-10-19 – 2014-10-21
    • Related Report
      2014 Research-status Report
  • [Presentation] Endogenous TDP-43 over-expression model with disrupted auto-regulation2014

    • Author(s)
      Akihiro Sugai, Taisuke Kato, Akihide Koyama, Masatoyo Nishizawa, Osamu Onodera
    • Organizer
      10th Annual Meeting of the Oligonucleotide Therapeutics Society.
    • Place of Presentation
      Hilton San Diego Resort & Spa, San Diego, California USA
    • Year and Date
      2014-10-12 – 2014-10-15
    • Related Report
      2014 Research-status Report
  • [Presentation] Update in amyotrophic lateral sclerosis:2014

    • Author(s)
      Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi
    • Organizer
      The XVIII International Congress of Neuropathology.
    • Place of Presentation
      Rio de Janeiro, Brazil,
    • Year and Date
      2014-09-14 – 2014-09-18
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] RNA metabolism and ALS.2014

    • Author(s)
      Osamu Onodera
    • Organizer
      The 37th Annual Meeting of the Japan Neuroscience Society.
    • Place of Presentation
      横浜 パシフィコ横浜
    • Year and Date
      2014-09-11 – 2014-09-13
    • Related Report
      2014 Research-status Report
    • Invited

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

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