Molecular mechanisms of neurocircuit in motor neuron diseases

2019 Fiscal Year Final Research Report

• 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
• Keywords: 球脊髄性筋萎縮症 / Srcシグナル異常 / Src阻害薬

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.

Free Research Field

運動ニューロン疾患

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。