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Identification for serum biomarker for ALS associated with the function of TDP-43

Research Project

Project/Area Number 22659169
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeSingle-year Grants
Research Field Neurology
Research InstitutionNiigata University

Principal Investigator

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

Project Period (FY) 2010 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥3,190,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥390,000)
Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2010: ¥1,500,000 (Direct Cost: ¥1,500,000)
Keywords神経分子病態学 / TDP-43 / ALS / グリア / スプライシング / マイクロアレイ
Research Abstract

Amyotrophic lateral sclerosis(ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa(TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP-43 function. Using exon array analysis, we observed a remarkable alteration of splicing in several genes as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type splicing variants decreased and transcripts lacking some exons increased. The RNA binding ability of TDP-43 was necessary for inclusion and exclusion of these exons. Moreover, we found an increment of splicing varinats in motor cortex, spinal cord and spinal motor neurons collected by laser microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS.

Report

(3 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report
  • Research Products

    (21 results)

All 2012 2011 2010 Other

All Journal Article (6 results) (of which Peer Reviewed: 1 results) Presentation (15 results)

  • [Journal Article] Co-occurrence of argyrophilic grain disease in sporadic amyotrophic lateral sclerosis2012

    • Author(s)
      Soma K, Fu YJ, Wakabayashi K, Onodera O, Kakita A, Takahashi H
    • Journal Title

      Neuropathology

      Volume: 38 Pages: 54-60

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
  • [Journal Article] 家族性ALS ALS10(遺伝性ALS-TDP)の臨床と病理2011

    • Author(s)
      今野卓哉, 石原智彦, 西澤正豊, 小野寺理
    • Journal Title

      Clinical Neuroscience

      Volume: 29巻 Pages: 1019-1021

    • Related Report
      2011 Final Research Report
  • [Journal Article] Primary lateral sclerosis : Upper-motor-predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration-immunohistochemical and biochemical analyses of TDP-432011

    • Author(s)
      Kosaka T, Fu YJ, Shiga A, Ishidaira H, Tan CF, Tani T, Koike R, Onodera O, Nishizawa M, Kakita A, Takahashi H
    • Journal Title

      Neuropathology. 2011

      Volume: 32 Issue: 4 Pages: 373-384

    • DOI

      10.1111/j.1440-1789.2011.01271.x

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] 家族性ALS ALS10(遺伝性ALS-TDP)の臨床と病理2011

    • Author(s)
      今野卓哉, 石原智彦, 西津正豊, 小野寺理
    • Journal Title

      Clinical Neuroscience

      Volume: 29巻9号 Pages: 1019-1021

    • Related Report
      2011 Annual Research Report
  • [Journal Article] ALS Update ALSの病態FUSの観点から2010

    • Author(s)
      志賀篤, 西澤正豊, 小野寺理
    • Journal Title

      医学のあゆみ

      Volume: 253 Pages: 236-240

    • Related Report
      2010 Annual Research Report
  • [Journal Article] 【神経変性疾患におけるTDP-43】家族性筋萎縮性側索硬化症とTDP-432010

    • Author(s)
      石原智彦, 横関明男, 西澤正豊, 高橋均, 小野寺理
    • Journal Title

      最新医学

      Volume: 65 Pages: 1648-1653

    • Related Report
      2010 Annual Research Report
  • [Presentation] Tardbp欠損マウスのmRNA選択的スプライシングと組織特異的な多様性 Tardbp alternatively spliced mRNA and tissue-specific variation in heterozygous Tardbp-deficient mice2011

    • Author(s)
      廣川祥子, 佐藤俊哉, 石原知彦, 藤野赳至, 近藤千草, 横山峯介, 崎村健司, 西澤正豊, 小野寺理
    • Organizer
      分子生物学会
    • Place of Presentation
      横浜
    • Year and Date
      2011-12-14
    • Related Report
      2011 Annual Research Report
  • [Presentation] ALS関連蛋白TDP-43の自己発現調節機能に関与するスプライシング因子の検討Splicing factors involved in an autoregulation of the ALS-associated protein TDP-432011

    • Author(s)
      桑原美咲, 石原智彦, 志賀篤, 今野卓哉, 小山哲秀, 西澤正豊, 小野寺理
    • Organizer
      分子生物学会
    • Place of Presentation
      横浜
    • Year and Date
      2011-12-14
    • Related Report
      2011 Annual Research Report
  • [Presentation] Aberrant splicing of POLDIP3 gene in motor neuron with ALS2011

    • Author(s)
      A.SHIGA, T.ISHIHARA, A.MIYASHITA, T.KATO, M.KUWABARA, A.YOKOSEKI, R.KUWANO, A.KAITA, H.TAKAHASHI, M.NISHIZAWA, O.ONODERAKA
    • Organizer
      Neuroscience 2011
    • Place of Presentation
      Washington, D.C.
    • Year and Date
      2011-11-13
    • Related Report
      2011 Annual Research Report
  • [Presentation] Alteration of snRNAs in amyotrophic lateral sclerosis2011

    • Author(s)
      T.ISHIHARA, A.SHIGA, A.KAKITA, A.YOKOSEKI, M.NISHIZAWA, H.TAKAHASHI, O.ONODERA
    • Organizer
      Neuroscience 2011
    • Place of Presentation
      Washington, D.C.
    • Year and Date
      2011-11-12
    • Related Report
      2011 Annual Research Report
  • [Presentation] Alteration of snRNAs in amyotrophic lateral sclerosis2011

    • Author(s)
      T.ISHIHARA, A.SHIGA, A.KAKITA, A.YOKOSEKI, M.NISHIZAWA, H.TAKAHASHI, O.ONODERA
    • Organizer
      6th Brain Research Conference : RNA-Binding Proteins in Neurological Disease
    • Place of Presentation
      Washington, D.C.
    • Year and Date
      2011-11-10
    • Related Report
      2011 Annual Research Report
  • [Presentation] Aberrant splicing of POLDIP3 gene in motor neuron with ALS2011

    • Author(s)
      A.SHIGA, T.ISHIHARA, A.MIYASHITA, T.KATO, M.KUWABARA, A.YOKOSEKI, R.KUWANO, A.KAKITA, H.TAKAHASHI, M.NISHIZAWA, O.ONODERA
    • Organizer
      6th Brain Research Conference : RNA-Binding Proteins in Neurological Disease
    • Place of Presentation
      Washington, D.C.
    • Year and Date
      2011-11-10
    • Related Report
      2011 Annual Research Report
  • [Presentation] Alteration of snRNAs in amyotrophic lateral sclerosis 20112011

    • Author(s)
      T. ISHIHARA, A. SHIGA, A. KAKITA, A. YOKOSEKI, M. NISHIZAWA, H. TAKAHASHI, O. ONODERA
    • Organizer
      米国神経科学会
    • Related Report
      2011 Final Research Report
  • [Presentation] Aberrant splicing of POLDIP3 gene in motor neuron with ALS2011

    • Author(s)
      A. SHIGA, T. ISHIHARA, A. MIYASHITA, T. KATO, M. KUWABARA, A. YOKOSEKI, R. KUWANO, A. KAKITA, H. TAKAHASHI, M. NISHIZAWA, O. ONODERA
    • Organizer
      米国神経科学会
    • Related Report
      2011 Final Research Report
  • [Presentation] Alteration of snRNAs in amyotrophic lateral sclerosis2011

    • Author(s)
      T. ISHIHARA, A. SHIGA, A. KAKITA, A. YOKOSEKI, M. NISHIZAWA, H. TAKAHASHI, O. ONODERA
    • Organizer
      6th Brain Research Conference : RNA-Binding Proteins in Neurological Disease
    • Related Report
      2011 Final Research Report
  • [Presentation] Aberrant splicing of POLDIP3 gene in motor neuron with ALS2011

    • Author(s)
      A. SHIGA, T. ISHIHARA, A. MIYASHITA, T. KATO M. KUWABARA, A. YOKOSEKI, R. KUWANO, A. KAKITA, H. TAKAHASHI, M. NISHIZAWA, O. ONODERA
    • Organizer
      6th Brain Research Conference : RNA-Binding Proteins Neurological Disease
    • Related Report
      2011 Final Research Report
  • [Presentation] Tardbp欠損マウスのmRNA選択的スプライシングと組織特異的な多様性2011

    • Author(s)
      廣川祥子,佐藤俊哉,石原知彦,藤野赳至,近藤千草,横山峯介,崎村健司,西澤正豊,小野寺理
    • Organizer
      分子生物学会
    • Related Report
      2011 Final Research Report
  • [Presentation] TDP-43 depletion causes splicing defects in the genes associated with endomemb rane system.2010

    • Author(s)
      A.SHIGA, T.ISHIHARA, A.MWASHITA, M.YOKOO, Y ARIIZUMI, A.YOKOSEKI, R.KUWANO, M.NISHIZAWA, O.ONODERA
    • Organizer
      Neuroscience 2010
    • Place of Presentation
      San Diego
    • Year and Date
      2010-11-13
    • Related Report
      2010 Annual Research Report
  • [Presentation] Alteration of snRNAs in Amyotrophic Lateral Sclerosis2010

    • Author(s)
      Ishihara, T.Shiga, A.Kakita, A.Yokoseki, A.Nishizawa, M.Takahashi, H.Onodera, O
    • Organizer
      AAN 2010
    • Place of Presentation
      Toronto
    • Related Report
      2010 Annual Research Report
  • [Presentation] Cytoplasmic C-Terminus TDP-43 Aggregate Leads to Increased Phosphorylation of Full-Length TDP-43 in Culture Cell2010

    • Author(s)
      Ariizumi, Y..Ishihara ; T.Yokoo, M.Shiga, A.Yokoseki, A.Onodera, O.Nishizawa, M
    • Organizer
      AAN 2010
    • Place of Presentation
      Toronto
    • Related Report
      2010 Annual Research Report
  • [Presentation] ALS関連蛋白TDP-43の自己発現調節機能に関与するスプライシング因子の検討

    • Author(s)
      桑原美咲,石原智彦,志賀篤,今野卓哉,小山哲秀,西澤正豊,小野寺理
    • Organizer
      分子生物学会
    • Related Report
      2011 Final Research Report

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Published: 2010-08-23   Modified: 2016-04-21  

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