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Epigenetic mechanism on the pathogenesis of motor neuron disease

Research Project

Project/Area Number 26860665
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Neurology
Research InstitutionNagoya University

Principal Investigator

Kondo Naohide  名古屋大学, 医学部附属病院, 医員 (20725527)

Project Period (FY) 2014-04-01 – 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: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords球脊髄性筋萎縮症 / エピジェネティクス / DNAメチル化 / DNAメチル化酵素 / DNAメチル化阻害剤 / 神経変性疾患 / 運動ニューロン疾患 / CpGアイランド / Hsp70 / 分子シャペロン
Outline of Final Research Achievements

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neuromuscular disease caused by the expansion of a CAG repeat within the first exon of androgen receptor (AR) gene. DNA methylation is the fundamental silencing machinery for several genes with a CpG-rich promoter. The hypothesis of this study is an abnormal DNA hypermethylation in the CpG island of several gene promoters contributes to the transcriptional dysfunction of SBMA. Immunohistochemistry analysis revealed that DNA methyltransferase 1(Dnmt1) expression level of spinal motor neuron in SBMA model mouse was up-regulated compared with that of wild type mouse. RG108, a DNA methyltransferase inhibitor, improved the cell viability of the SBMA model cells. Intraventricular injection of RG108 also mitigated the mortality and motor dysfunction of the model mice. These results indicate that pharmacological blockade of DNA methylation is a therapeutic candidate for SBMA.

Report

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

    (13 results)

All 2016 2015 2014

All Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Acknowledgement Compliant: 3 results,  Open Access: 2 results) Presentation (6 results) Book (1 results)

  • [Journal Article] BIIB021, a synthetic Hsp90 inhibitor, induces mutant ataxin-1 degeneration through the activation of heat shock factor 1.2016

    • Author(s)
      Ding Y, Adachi H, Katsuno M, Sahashi K, Kondo N, Iida M, Tohnai G, Nakatsuji H, Sobue G
    • Journal Title

      Neuroscience

      Volume: S0306-4522 Pages: 30051-30053

    • DOI

      10.1016/j.neuroscience.2016.03.064

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Hemodialysis-related Portal-Systemic Encephalopathy2015

    • Author(s)
      Kondo N, Ito Y, Yamashita H, Azuma F, Nokura K, Yasuda T, Sobue G
    • Journal Title

      Internal Medicine

      Volume: 54 Issue: 9 Pages: 1113-1117

    • DOI

      10.2169/internalmedicine.54.0267

    • NAID

      130005068313

    • ISSN
      0918-2918, 1349-7235
    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration.2015

    • Author(s)
      Ding Y, Adachi H, Katsuno M, Huang Z, Jiang YM, Kondo N, Iida M, Tohnai G, Nakatsuji H, Funakoshi H, Nakamura T, Sobue G
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 468 Issue: 4 Pages: 677-683

    • DOI

      10.1016/j.bbrc.2015.11.015

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy.2015

    • Author(s)
      Sahashi K, Katsuno M, Hung G, Adachi H, Kondo N, Nakatsuji H, Tohnai G, Iida M, Bennett CF, Sobue G.
    • Journal Title

      Hum Mol Genet.

      Volume: 24(21) Issue: 21 Pages: 5985-94

    • DOI

      10.1093/hmg/ddv300

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Pioglitazone suppresses neuronal and muscular degeneration caused by polyglutamine-expanded androgen receptors.2015

    • Author(s)
      Iida M, Katsuno M, Nakatsuji H, Adachi H, Kondo N, Miyazaki Y, Tohnai G, Ikenaka K, Watanabe H, Yamamoto M, Kishida K, Sobue G
    • Journal Title

      Hum Mol Genet.

      Volume: 24 Issue: 2 Pages: 314-329

    • DOI

      10.1093/hmg/ddu445

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Paeoniflorin eliminates a mutant AR via NF-YA-dependent proteolysis in spinal and bulbar muscular atrophy.2014

    • Author(s)
      Tohnai G, Adachi H, Katsuno M, Doi H, Matsumoto S, Kondo N, Miyazaki Y, Iida M, Nakatsuji H, Qiang Q, Ding Y, Watanabe H, Yamamoto M, Ohtsuka K, Sobue G.
    • Journal Title

      Hum Mol Genet.

      Volume: 23 Issue: 13 Pages: 3552-3565

    • DOI

      10.1093/hmg/ddu066

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Role of aberrant DNA methylation in the pathogenesis of spinal and bulbar muscular atrophy.2016

    • Author(s)
      Kondo N, Katsuno M, Adachi H, Sahashi K, Iida M, Nakatsuji H, Tohnai G, Sobue G.
    • Organizer
      第8回NAGOYAグローバルリトリート
    • Place of Presentation
      あいち健康プラザ(愛知県知多郡)
    • Year and Date
      2016-02-12
    • Related Report
      2015 Annual Research Report
  • [Presentation] DNAメチル化阻害剤による球脊髄性筋萎縮症の治療法開発2015

    • Author(s)
      近藤直英、勝野雅央、足立弘明、佐橋健太郎、飯田円、中辻秀朗、藤内玄規、祖父江元
    • Organizer
      第33回日本神経治療学会総会
    • Place of Presentation
      名古屋国際会議場(愛知県名古屋市)
    • Year and Date
      2015-11-26
    • Related Report
      2015 Annual Research Report
  • [Presentation] DNAメチル化阻害剤(RG108)による遺伝性運動ニューロン疾患治療2015

    • Author(s)
      近藤直英、勝野雅央、足立弘明、佐橋健太郎、飯田円、中辻秀朗、藤内玄規、祖父江元
    • Organizer
      第5回名古屋大学・生理学研究所合同シンポジウム
    • Place of Presentation
      生理学研究所(愛知県岡崎市)
    • Year and Date
      2015-09-19
    • Related Report
      2015 Annual Research Report
  • [Presentation] Epigenetic treatment of polyglutamine-induced motor neuron disease.2015

    • Author(s)
      Kondo N, Katsuno M, Adachi H, Sahashi K, Iida M, Nakatsuji H, Tohnai G, Sobue G.
    • Organizer
      第56回日本神経学会学術大会
    • Place of Presentation
      朱鷺メッセ(新潟県新潟市)
    • Year and Date
      2015-05-20
    • Related Report
      2015 Annual Research Report
  • [Presentation] Role of aberrant DNA methylation in the pathogenesis of spinal and bulbar muscular atrophy2015

    • Author(s)
      近藤直英,勝野雅央,佐橋健太郎,飯田円,中辻秀朗,藤内玄規,祖父江元
    • Organizer
      第7回NAGOYAグローバルリトリート
    • Place of Presentation
      愛知県大府市(愛知健康プラザ)
    • Year and Date
      2015-02-13 – 2015-02-14
    • Related Report
      2014 Research-status Report
  • [Presentation] DNAメチル化阻害剤が球脊髄性筋萎縮症の病態に与える影響の解析2014

    • Author(s)
      近藤直英,勝野雅央,足立弘明,佐橋健太郎,飯田円,中辻秀朗,藤内玄規,祖父江元
    • Organizer
      第55回日本神経学会学術大会
    • Place of Presentation
      福岡県福岡市(福岡国際会議場・福岡サンパレス・福岡国際センター)
    • Year and Date
      2014-05-21 – 2014-05-24
    • Related Report
      2014 Research-status Report
  • [Book] Heat Shock Factor, Chapter11 HSF Inhibits the Progression of Age-Related Neurodegenerative Diseases2016

    • Author(s)
      Nakai Akira (Ed.), Chapter11 Kondo Naohide, Katsuno Masahisa, Riku Yuichi,Sobue Gen
    • Total Pages
      292
    • Publisher
      Springer
    • Related Report
      2015 Annual Research Report

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Published: 2014-04-04   Modified: 2017-05-10  

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