Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy
Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy
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DOI：
10.1038/s41467-019-12282-7
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发表时间：
2019-09-19
影响因子：
16.6
通讯作者：
Katsuno, Masahisa
中科院分区：
文献类型：
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作者：
Iida, Madoka;Sahashi, Kentaro;Katsuno, Masahisa
脊髓延髓肌萎缩症（SBMA）是一种由雄激素受体（AR）基因CAG重复序列扩增引起的神经肌肉疾病。在这里，我们利用磷蛋白测定法对SBMA小鼠模型（AR-97 Q小鼠）中的信号通路进行了全面分析。我们在三个阶段测量了AR-97 Q小鼠脊髓和骨骼肌中17种磷酸化蛋白的水平。AR-97 Q小鼠脊髓和骨骼肌中磷酸化Src（p-Src）水平在发作前显著升高。腹腔注射Src激酶抑制剂可改善转基因小鼠的行为和组织病理学表型。我们确定p130 Cas作为Src的效应分子，并表明磷酸化的p130 Cas在SBMA的小鼠和细胞模型中升高。这些结果表明Src激酶抑制是SBMA的潜在治疗方法。
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. Here, we perform a comprehensive analysis of signaling pathways in a mouse model of SBMA (AR-97Q mice) utilizing a phosphoprotein assay. We measure the levels of 17 phosphorylated proteins in spinal cord and skeletal muscle of AR-97Q mice at three stages. The level of phosphorylated Src (p-Src) is markedly increased in the spinal cords and skeletal muscles of AR-97Q mice prior to the onset. Intraperitoneal administration of a Src kinase inhibitor improves the behavioral and histopathological phenotypes of the transgenic mice. We identify p130Cas as an effector molecule of Src and show that the phosphorylated p130Cas is elevated in murine and cellular models of SBMA. These results suggest that Src kinase inhibition is a potential therapy for SBMA.