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

被引：13

作者：

Iida, Madoka ^{[1
,2
]}

Sahashi, Kentaro ^{[1
]}

Kondo, Naohide ^{[1
]}

Nakatsuji, Hideaki ^{[1
]}

Tohnai, Genki ^{[1
]}

Tsutsumi, Yutaka ^{[1
]}

Noda, Seiya ^{[1
,3
]}

Murakami, Ayuka ^{[1
,3
]}

Onodera, Kazunari ^{[1
,4
]}

Okada, Yohei ^{[1
,4
,5
]}

Nakatochi, Masahiro ^{[6
]}

Okabe, Yuka Tsukagoshi ^{[7
]}

Shimizu, Shinobu ^{[7
]}

Mizuno, Masaaki ^{[7
]}

Adachi, Hiroaki ^{[8
]}

Okano, Hideyuki ^{[5
]}

Sobue, Gen ^{[9
]}

Katsuno, Masahisa ^{[1
]}

机构：

[1] Nagoya Univ, Grad Sch Med, Dept Neurol, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan

[2] Japan Soc Promot Sci, Chiyoda Ku, 5-3-1 Kojimachi, Tokyo 1020083, Japan

[3] Natl Hosp Org, Suzuka Natl Hosp, Dept Neurol, 3-2-1 Kasado, Suzuka, Mie 5138501, Japan

[4] Aichi Med Univ, Sch Med, Dept Neurol, 1 Karimata, Nagakute, Aichi 4801195, Japan

[5] Keio Univ, Sch Med, Dept Physiol, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan

[6] Nagoya Univ, Grad Sch Med, Dept Nursing, Higashi Ku, 1-1-20 Daiko Minami, Nagoya, Aichi 4618673, Japan

[7] Nagoya Univ Hosp, Dept Adv Med, 65 Tsurumai Cho, Nagoya, Aichi 4668560, Japan

[8] Univ Occupat & Environm Hlth, Sch Med, Dept Neurol, Yahatanichi Ku, 1-1 Iseigaoka, Kitakyushu, Fukuoka 8070804, Japan

[9] Nagoya Univ, Brain & Mind Res Ctr, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

MUTANT ANDROGEN RECEPTOR; FOCAL ADHESION KINASE; PROSTATE-CANCER; C-SRC; MOUSE MODEL; NATURAL-HISTORY; PROTEIN; ACTIVATION; DISEASE; BETA;

D O I：

10.1038/s41467-019-12282-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：15

共 69 条

[1] CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model [J].