The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice

Shuangshuang Sun; Yihui Shen; Xu Zhang; Ning Ding; Zhe Xu; Qijie Zhang; Lei Li

doi:10.1016/j.ymthe.2024.05.016

The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice

Mol Ther. 2024 May 10:S1525-0016(24)00318-6. doi: 10.1016/j.ymthe.2024.05.016. Online ahead of print.

Authors

Shuangshuang Sun¹, Yihui Shen¹, Xu Zhang¹, Ning Ding¹, Zhe Xu¹, Qijie Zhang², Lei Li³

Affiliations

¹ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
² Department of Neurology, Fujian Institute of Neurology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China;. Electronic address: qijiezhang86@fjmu.edu.cn.
³ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China;. Electronic address: qijiezhang86@fjmu.edu.cn.

PMID: 38734896
DOI: 10.1016/j.ymthe.2024.05.016

Abstract

The disassembly of the neuromuscular junction (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), ultimately leading to motor dysfunction and lethal respiratory paralysis. The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common genetic mutation, and the dipeptide repeat (DPR) proteins have been shown to cause neurodegeneration. While no drugs can treat ALS patients efficiently, new treatment strategies are urgently needed. Here, we report that a MuSK agonist antibody alleviates poly-PR-induced NMJ deficits in C9orf72-ALS mice. The HB9-PR^F/F mice, which express poly-PR proteins in motor neurons, exhibited impaired motor behavior and NMJ deficits. Mechanistically, poly-PR proteins interacted with Agrin to disrupt the interaction between Agrin and Lrp4, leading to attenuated activation of MuSK. Treatment with a MuSK agonist antibody rescued NMJ deficits, and extended the lifespan of C9orf72-ALS mice. Moreover, impaired NMJ transmission was observed in C9orf72-ALS patients. These findings identify the mechanism by which poly-PR proteins attenuate MuSK activation and NMJ transmission, highlighting the potential of promoting MuSK activation with an agonist antibody as a therapeutic strategy to protect NMJ function and prolong the lifespan of ALS patients.