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

Research output: Contribution to journalArticle

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 languageEnglish
Number of pages1
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019 Sep 19

Fingerprint

Atrophic Muscular Disorders
atrophy
degeneration
Androgen Receptors
mice
src-Family Kinases
skeletal muscle
spinal cord
Muscle
Spinal Cord
muscles
Skeletal Muscle
Neuromuscular Diseases
Phosphoproteins
effectors
phenotype
Transgenic Mice
Assays
Genes
genes

ASJC Scopus subject areas

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

Cite this

Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy. / Iida, Madoka; Sahashi, Kentaro; Kondo, Naohide; Nakatsuji, Hideaki; Tohnai, Genki; Tsutsumi, Yutaka; Noda, Seiya; Murakami, Ayuka; Onodera, Kazunari; Okada, Yohei; Nakatochi, Masahiro; Tsukagoshi Okabe, Yuka; Shimizu, Shinobu; Mizuno, Masaaki; Adachi, Hiroaki; Okano, Hideyuki; Sobue, Gen; Katsuno, Masahisa.

In: Nature communications, Vol. 10, No. 1, 19.09.2019.

Research output: Contribution to journalArticle

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. https://doi.org/10.1038/s41467-019-12282-7
Iida, Madoka ; Sahashi, Kentaro ; Kondo, Naohide ; Nakatsuji, Hideaki ; Tohnai, Genki ; Tsutsumi, Yutaka ; Noda, Seiya ; Murakami, Ayuka ; Onodera, Kazunari ; Okada, Yohei ; Nakatochi, Masahiro ; Tsukagoshi Okabe, Yuka ; Shimizu, Shinobu ; Mizuno, Masaaki ; Adachi, Hiroaki ; Okano, Hideyuki ; Sobue, Gen ; Katsuno, Masahisa. / Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy. In: Nature communications. 2019 ; Vol. 10, No. 1.
@article{c924c09cbad3410fa429560bcca4680c,
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",
year = "2019",
month = "9",
day = "19",
doi = "10.1038/s41467-019-12282-7",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

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

PY - 2019/9/19

Y1 - 2019/9/19

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.

UR - http://www.scopus.com/inward/record.url?scp=85072402527&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072402527&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-12282-7

DO - 10.1038/s41467-019-12282-7

M3 - Article

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

ER -