Epigenetic mechanism on the pathogenesis of motor neuron disease

• Project/Area Number: 26860665
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Nagoya 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: ¥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.

Research Products

• [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
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hemodialysis-related Portal-Systemic Encephalopathy (2015)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
• [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
• [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
• [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
• [Presentation] Role of aberrant DNA methylation in the pathogenesis of spinal and bulbar muscular atrophy (2015)
  • 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
• [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
• [Book] Heat Shock Factor, Chapter11 HSF Inhibits the Progression of Age-Related Neurodegenerative Diseases (2016)
  • Author(s): Nakai Akira (Ed.), Chapter11 Kondo Naohide, Katsuno Masahisa, Riku Yuichi,Sobue Gen
  • Total Pages: 292
  • Publisher: Springer