Sarcoglycan Alpha Mitigates Neuromuscular Junction Decline in Aged Mice by Stabilizing LRP4
- Kai Zhao1,3,*,
- Chengyong Shen3,4,*,
- Lei Li1,3,5,
- Haitao Wu3,6,
- Guanglin Xing1,
- Zhaoqi Dong1,
- Hongyang Jing1,
- Wenbing Chen1,
- Hongsheng Zhang1,
- Zhibing Tan1,
- Jinxiu Pan1,
- Lei Xiong1,
- Hongsheng Wang1,
- Wanpeng Cui1,
- Xiang-Dong Sun3,7,
- Shihua Li8,
- Xinping Huang9,
- Wen-Cheng Xiong1,2,3, and
- Lin Mei1,2,3
- 1Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106,
- 2Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106,
- 3Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912,
- 4Institute of Translational Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, China 310020,
- 5School of Life Science and Technology, Shanghai Tech University, Shanghai, China 201210,
- 6Department of Neurobiology, Institute of Basic Medical Sciences, Beijing, China 100850,
- 7Department of Neurology, School of Basic Medical Sciences, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China 510260,
- 8Department of Human Genetics, School of Medicine, Emory University, Atlanta, Georgia 30322, and
- 9Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, Georgia, 30322
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Author contributions: K.Z. wrote the first draft of the paper; K.Z. edited the paper; K.Z., W.-C.X., and L.M. designed research; K.Z., C.S., L.L., H.W., G.X., Z.D., H.J., W.-B.C., H.Z., Z.T., J.P., L.X., H.-S.W., W.C., and X.-D.S. performed research; H.W., S.L., X.H., W.-C.X., and L.M. contributed unpublished reagents/analytic tools; K.Z., C.S., L.L., H.W., G.X., Z.-Q.D., H.J., W.-B.C., H.Z., Z.T., J.-X.P., L.X., H.-S.W., W.C., and X.-D.S. analyzed data; K.Z., C.S., Z.-Q.D., and L.M. wrote the paper.
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↵*K.Z. and C.S. contributed equally to this work.
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.
- Received April 3, 2018.
- Revision received August 7, 2018.
- Accepted August 22, 2018.
- Copyright © 2018 the authors 0270-6474/18/388860-14$15.00/0
