Molecular mechanisms of neurocircuit in motor neuron diseases

• Project/Area Number: 18K15361
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Nagoya University
• Principal Investigator: Iida Madoka 名古屋大学, 医学系研究科, 学振特別研究員(RPD) (40815437)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 球脊髄性筋萎縮症 / Srcシグナル異常 / Src阻害薬 / SBMA / Cre-loxPシステム / Srcシグナル / アンドロゲン受容体 / 後根神経節 / 感覚ニューロン / 運動ニューロンネットワーク変性

Outline of Final Research Achievements

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, progressive neuromuscular disease caused by the expanded CAG repeats in the androgen receptor (AR) gene. We performed a comprehensive analysis of signaling pathways in a mouse model of SBMA (AR-97Q mice) and revealed thattThe level of phosphorylated Src (p-Src) was markedly increased in the spinal cords and skeletal muscles of AR-97Q mice prior to the onset. Src phosphorylation was also elevated in motor neurons and skeletal muscles of the patients with SBMA. We identified p130Cas as effector molecules of Src. We also revealed that the interaction between Src and AR plays an essential role in the activation of Src pathway in the pathogenesis of SBMA. Finally, the administration of compound X, a novel SKI, ameliorated the neurological phenotype of the mouse model of SBMA.

Academic Significance and Societal Importance of the Research Achievements

Src阻害薬はSBMAの新規治療薬として有望であると考えられた。Srcは様々な癌で活性化し癌の進行や転移に関連することが知られており、Src阻害薬の中には癌の治療薬として臨床応用されている薬剤もしくは治験中の薬剤が複数存在する。本研究は神経筋疾患と癌の共通項を見出し、Src阻害薬が神経難病や癌の治療薬となりうる新たな可能性を示唆した。

Research Products

• [Journal Article] Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy (2019)
  • Author(s): Iida Madoka、Sahashi Kentaro、Kondo Naohide、Nakatsuji Hideaki、Tohnai Genki、Tsutsumi Yutaka、Noda Seiya、Murakami Ayuka、Onodera Kazunari、Okada Yohei、Nakatochi Masahiro、Tsukagoshi Okabe Yuka、Shimizu Shinobu、Mizuno Masaaki、Adachi Hiroaki、Okano Hideyuki、Sobue Gen、Katsuno Masahisa
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 4262-4262
  • DOI: 10.1038/s41467-019-12282-7
  • Peer Reviewed / Open Access
• [Journal Article] DNA methylation inhibitor attenuates polyglutamine-induced neurodegeneration by regulating Hes5 (2019)
  • Author(s): Kondo N, Tohnai G, Sahashi K, Iida M, Kataoka M, Nakatsuji H, Tsutsumi Y, Hashizume A, Adachi H, Koike H, Shinjo K, Kondo Y, Sobue G, Katsuno M.
  • Journal Title: EMBO Mol Med Volume: none Issue: 5
  • DOI: 10.15252/emmm.201708547
  • Peer Reviewed / Open Access
• [Journal Article] Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis. (2019)
  • Author(s): Ito D, Hashizume A, Hijikata Y, Yamada S, Iguchi Y, Iida M, Kishimoto Y, Moriyoshi H, Hirakawa A, Katsuno M.
  • Journal Title: J Neurol. Volume: 266 Issue: 12 Pages: 2952-2961
  • DOI: 10.1007/s00415-019-09507-6
  • NAID: 120006786260
  • Peer Reviewed
• [Presentation] Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy (2019)
  • Author(s): Madoka Iida, Kentaro Sahashi, Naohide Kondo, Hideaki Nakatsuji, Genki Tohnai, Masahisa Katsuno
  • Organizer: 第42回日本神経科学大会
• [Presentation] Molecular mechanisms of neuromuscular degeneration in spinal and bulbar muscular atrophy (2019)
  • Author(s): Madoka Iida
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy (2019)
  • Author(s): Madoka Iida, Kentaro Sahashi, Naohide Kondo, Hideaki Nakatsuji, Genki Tohnai, Masahisa Katsuno
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy (2019)
  • Author(s): Madoka Iida, Kentaro Sahashi, Naohide Kondo, Hideaki Nakatsuji, Genki Tohnai, Gen Sobue, Masahisa Katsuno
  • Organizer: AMED-MRCシンポジウム
  • Int'l Joint Research
• [Presentation] Development of the therapeutics targeting the spatiotemporal dysregulation of signaling pathways in spinal and bulbar muscular atrophy (2018)
  • Author(s): Madoka Iida, Kentaro Sahashi, Naohide Kondo, Hideaki Nakatsuji, Genki Tohnai, Yutaka Tsutsumi, Masahisa Katsuno
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] Development of the therapeutics targeting the spatiotemporal dysregulation of signaling pathways in spinal and bulbar muscular atrophy (2018)
  • Author(s): Madoka Iida, Kentaro Sahashi, Naohide Kondo, Hideaki Nakatsuji, Genki Tohnai, Yutaka Tsutsumi, Masahisa Katsuno
  • Organizer: 第41回日本神経科学大会