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

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Kai ZhaoLin Mei

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 ...Continue Reading

Citations

Jun 2, 2020·PLoS Biology·Lei XiongWen-Cheng Xiong
Sep 11, 2020·Nature Communications·Daniel J HamMarkus A Rüegg
Dec 29, 2020·Frontiers in Aging Neuroscience·Zhengyuan BaoWing-Hoi Cheung
Dec 22, 2020·Frontiers in Molecular Neuroscience·Pedro M Rodríguez CruzAngela Vincent
Dec 18, 2020·Frontiers in Molecular Neuroscience·Yomna Badawi, Hiroshi Nishimune
Feb 15, 2020·Neuroscience Letters·Dina C Belhasan, Mohammed Akaaboune
Mar 7, 2021·International Journal of Molecular Sciences·Bisei OhkawaraKinji Ohno
Jul 30, 2021·Biogerontology·Alexandra Moreira-PaisJosé A Duarte
Aug 8, 2021·International Journal of Molecular Sciences·Shama R IyerRichard M Lovering

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Signaling by Tyrosine Kinases

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. RTKs have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Discover the latest research on cell signaling and RTK here.