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; Masahisa Katsuno

doi:10.1038/s41467-019-12282-7

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, Masahisa Katsuno

Department of Physiology

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

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.

Original language	English
Article number	4262
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12282-7
Publication status	Published - 2019 Dec 1

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-019-12282-7

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Iida, M., Sahashi, K., Kondo, N., Nakatsuji, H., Tohnai, G., Tsutsumi, Y., Noda, S., Murakami, A., Onodera, K., Okada, Y., Nakatochi, M., Tsukagoshi Okabe, Y., Shimizu, S., Mizuno, M., Adachi, H., Okano, H., Sobue, G., & Katsuno, M. (2019). Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy. Nature communications, 10(1), Article 4262. https://doi.org/10.1038/s41467-019-12282-7

Iida, M, Sahashi, K, Kondo, N, Nakatsuji, H, Tohnai, G, Tsutsumi, Y, Noda, S, Murakami, A, Onodera, K, Okada, Y, Nakatochi, M, Tsukagoshi Okabe, Y, Shimizu, S, Mizuno, M, Adachi, H, Okano, H, Sobue, G & Katsuno, M 2019, 'Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy', Nature communications, vol. 10, no. 1, 4262. https://doi.org/10.1038/s41467-019-12282-7

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title = "Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy",

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.",

author = "Madoka Iida and Kentaro Sahashi and Naohide Kondo and Hideaki Nakatsuji and Genki Tohnai and Yutaka Tsutsumi and Seiya Noda and Ayuka Murakami and Kazunari Onodera and Yohei Okada and Masahiro Nakatochi and {Tsukagoshi Okabe}, Yuka and Shinobu Shimizu and Masaaki Mizuno and Hiroaki Adachi and Hideyuki Okano and Gen Sobue and Masahisa Katsuno",

note = "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: {\textcopyright} 2019, The Author(s).",

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doi = "10.1038/s41467-019-12282-7",

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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.

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ER -

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

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