Sarcoglycan Alpha Mitigates Neuromuscular Junction Decline in Aged Mice by Stabilizing LRP4

被引：48

作者：

Zhao, Kai ^{[1
,3
]}

Shen, Chengyong ^{[3
,4
]}

Li, Lei ^{[1
,3
,5
]}

Wu, Haitao ^{[3
,6
]}

Xing, Guanglin ^{[1
]}

Dong, Zhaoqi ^{[1
]}

Jing, Hongyang ^{[1
]}

Chen, Wenbing ^{[1
]}

Zhang, Hongsheng ^{[1
]}

Tan, Zhibing ^{[1
]}

Pan, Jinxiu ^{[1
]}

Xiong, Lei ^{[1
]}

Wang, Hongsheng ^{[1
]}

Cui, Wanpeng ^{[1
]}

Sun, Xiang-Dong ^{[3
,7
]}

Li, Shihua ^{[8
]}

Huang, Xinping ^{[9
]}

Xiong, Wen-Cheng ^{[1
,2
,3
]}

Mei, Lin ^{[1
,2
,3
]}

机构：

[1] Case Western Reserve Univ, Sch Med, Dept Neurosci, 10900 Euclid Ave, Cleveland, OH 44106 USA

[2] Louis Stokes Cleveland Vet Affairs Med Ctr, Cleveland, OH 44106 USA

[3] Augusta Univ, Med Coll Georgia, Dept Neurosci & Regenerat Med, Augusta, GA 30912 USA

[4] Zhejiang Univ, Affiliated Hosp 1, Inst Translat Med, 268 Kaixuan Rd, Hangzhou 310020, Zhejiang, Peoples R China

[5] Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

[6] Inst Basic Med Sci, Dept Neurobiol, Beijing 100850, Peoples R China

[7] Guangzhou Med Univ, Affiliated Hosp 2, Sch Basic Med Sci, Dept Neurol, Guangzhou 510260, Guangdong, Peoples R China

[8] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA

[9] Emory Univ, Ctr Neurodegenerat Dis, Sch Med, Atlanta, GA 30322 USA

来源：

JOURNAL OF NEUROSCIENCE | 2018年 / 38卷 / 41期

关键词：

aging; LRP4; neuromuscular junction; SG alpha; DYSTROPHIN-GLYCOPROTEIN COMPLEX; DUCHENNE MUSCULAR-DYSTROPHY; SKELETAL-MUSCLE FIBERS; TYROSINE KINASE MUSK; MYASTHENIA-GRAVIS; MOTOR UNIT; AGRIN RECEPTOR; DEFICIENT MICE; RAT MUSCLE; END-PLATES;

D O I：

10.1523/JNEUROSCI.0860-18.2018

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

During aging, acetylcholine receptor (AChR) clusters become fragmented and denervated at the neuromuscular junction (NMJ). Under-pinning molecular mechanisms are not well understood. We showed that LRP4, a receptor for agrin and critical for NMJ formation and maintenance, was reduced at protein level in aged mice, which was associated with decreased MuSK tyrosine phosphorylat ion, suggesting compromised agrin-LRP4-MuSK signaling in aged muscles. Transgenic expression of LRP4 in muscles alleviated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. LRP4 ubiquitination was augmented in aged muscles, suggesting increased LRP4 degradation as a mechanism for reduced LRP4. We found that sarcoglycan alpha (SG alpha) interacted with LRP4 and delayed LRP4 degradation in cotransfected cells. AAV9-mediated expression of SG alpha in muscles mitigated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. These observations support a model where compromised agrinLRP4-MuSK signaling serves as a pathological mechanism of age-related NMJ decline and identify a novel function of SG alpha in stabilizing LRP4 for NMJ stability in aged mice.

引用

页码：8860 / 8873

页数：14

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