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.

Details

Title
Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy
Author
Iida, Madoka 1 ; Sahashi, Kentaro 2 ; Kondo, Naohide 2 ; Nakatsuji, Hideaki 2 ; Tohnai, Genki 2 ; Tsutsumi, Yutaka 2 ; Noda, Seiya 3 ; Murakami, Ayuka 3 ; Onodera, Kazunari 4 ; Okada, Yohei 5 ; Nakatochi, Masahiro 6   VIAFID ORCID Logo  ; Yuka Tsukagoshi Okabe 7 ; Shimizu, Shinobu 7 ; Mizuno, Masaaki 7 ; Adachi, Hiroaki 8   VIAFID ORCID Logo  ; Okano, Hideyuki 9 ; Sobue, Gen 10   VIAFID ORCID Logo  ; Katsuno, Masahisa 2   VIAFID ORCID Logo 

1  Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya city, Aichi, Japan; Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo, Japan 
2  Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya city, Aichi, Japan 
3  Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya city, Aichi, Japan; Department of Neurology, National Hospital Organization Suzuka National Hospital, Suzuka city, Mie, Japan 
4  Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya city, Aichi, Japan; Department of Neurology, Aichi Medical University School of Medicine, Nagakute-city, Aichi, Japan 
5  Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya city, Aichi, Japan; Department of Neurology, Aichi Medical University School of Medicine, Nagakute-city, Aichi, Japan; Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan 
6  Department of Nursing, Nagoya University Graduate School of Medicine, Nagoya city, Aichi, Japan 
7  Department of Advanced Medicine, Nagoya University Hospital, Nagoya city, Aichi, Japan 
8  Department of Neurology, University of Occupational and Environmental Health School of Medicine, Kitakyushu-city, Fukuoka, Japan 
9  Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan 
10  Brain and Mind Research Center, Nagoya University, Nagoya city, Aichi, Japan 
Pages
1-15
Publication year
2019
Publication date
Sep 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-12282-7
ProQuest document ID
2293852027
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.