| Literature DB >> 30171091 |
Kai Zhao1,2, Chengyong Shen3,4, Lei Li1,2,5, Haitao Wu2,6, Guanglin Xing1, Zhaoqi Dong1, Hongyang Jing1, Wenbing Chen1, Hongsheng Zhang1, Zhibing Tan1, Jinxiu Pan1, Lei Xiong1, Hongsheng Wang1, Wanpeng Cui1, Xiang-Dong Sun2,7, Shihua Li8, Xinping Huang9, Wen-Cheng Xiong1,10,2, Lin Mei11,10,2.
Abstract
During aging, acetylcholine receptor (AChR) clusters become fragmented and denervated at the neuromuscular junction (NMJ). Underpinning 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 phosphorylation, 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 α (SGα) interacted with LRP4 and delayed LRP4 degradation in cotransfected cells. AAV9-mediated expression of SGα in muscles mitigated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. These observations support a model where compromised agrin-LRP4-MuSK signaling serves as a pathological mechanism of age-related NMJ decline and identify a novel function of SGα in stabilizing LRP4 for NMJ stability in aged mice.SIGNIFICANCE STATEMENT This study provides evidence that LRP4, a receptor of agrin that is critical for NMJ formation and maintenance, is reduced at protein level in aged muscles. Transgenic expression of LRP4 in muscles ameliorates AChR fragmentation and denervation and improves neuromuscular transmission in aged mice, demonstrating a critical role of the agrin-LRP4-MuSK signaling. Our study also reveals a novel function of SGα to prevent LRP4 degradation in aged muscles. Finally, we show that NMJ decline in aged mice can be mitigated by AAV9-mediated expression of SGα in muscles. These observations provide insight into pathological mechanisms of age-related NMJ decline and suggest that improved agrin-LRP4-MuSK signaling may be a target for potential therapeutic intervention.Entities:
Keywords: LRP4; SGα; aging; neuromuscular junction
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Year: 2018 PMID： 30171091 PMCID： PMC6181315 DOI： 10.1523/JNEUROSCI.0860-18.2018
Source DB: PubMed Journal: J Neurosci ISSN： 0270-6474 Impact factor: 6.167