TY - JOUR
T1 - Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy
AU - Iida, Madoka
AU - Sahashi, Kentaro
AU - Kondo, Naohide
AU - Nakatsuji, Hideaki
AU - Tohnai, Genki
AU - Tsutsumi, Yutaka
AU - Noda, Seiya
AU - Murakami, Ayuka
AU - Onodera, Kazunari
AU - Okada, Yohei
AU - Nakatochi, Masahiro
AU - Tsukagoshi Okabe, Yuka
AU - Shimizu, Shinobu
AU - Mizuno, Masaaki
AU - Adachi, Hiroaki
AU - Okano, Hideyuki
AU - Sobue, Gen
AU - Katsuno, Masahisa
N1 - Funding Information:
This work was funded by Grants-in-Aid (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Nos. 26293206, 16K15480, 17H04195, 17J40128, and 18K15361), grants from the Japan Agency for Medical Research and Development (AMED) (No. 17ek0109221h0001 and 18ek0109221h0002), a grant from the Naito Foundation, a grant from the Hori Sciences and Arts Foundation, Nagoya University Hospital Funding for Clinical Research and a grant from “The Acceleration Program for Intractable Diseases Research utilizing Disease-Specific iPS cells” to H.O. from AMED (No. 19bm0804003h0003). No other agencies provided funding, and the investigators had sole discretion over the study design; collection, analysis, and interpretation of data; writing of the report; and the decision to submit it for publication.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-12282-7
DO - 10.1038/s41467-019-12282-7
M3 - Article
C2 - 31537808
AN - SCOPUS:85072402527
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4262
ER -