Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy

Madoka Iida, Kentaro Sahashi, Naohide Kondo, Hideaki Nakatsuji, Genki Tohnai, Yutaka Tsutsumi, Seiya Noda, Ayuka Murakami, Kazunari Onodera, Yohei Okada, Masahiro Nakatochi, Yuka Tsukagoshi Okabe, Shinobu Shimizu, Masaaki Mizuno, Hiroaki Adachi, Hideyuki Okano, Gen Sobue and Masahisa Katsuno ()
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Madoka Iida: Nagoya University Graduate School of Medicine
Kentaro Sahashi: Nagoya University Graduate School of Medicine
Naohide Kondo: Nagoya University Graduate School of Medicine
Hideaki Nakatsuji: Nagoya University Graduate School of Medicine
Genki Tohnai: Nagoya University Graduate School of Medicine
Yutaka Tsutsumi: Nagoya University Graduate School of Medicine
Seiya Noda: Nagoya University Graduate School of Medicine
Ayuka Murakami: Nagoya University Graduate School of Medicine
Kazunari Onodera: Nagoya University Graduate School of Medicine
Yohei Okada: Nagoya University Graduate School of Medicine
Masahiro Nakatochi: Nagoya University Graduate School of Medicine
Yuka Tsukagoshi Okabe: Nagoya University Hospital
Shinobu Shimizu: Nagoya University Hospital
Masaaki Mizuno: Nagoya University Hospital
Hiroaki Adachi: University of Occupational and Environmental Health School of Medicine
Hideyuki Okano: Keio University School of Medicine
Gen Sobue: Nagoya University
Masahisa Katsuno: Nagoya University Graduate School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12282-7

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