上海科技大学知识管理系统

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 ef fi- ciently, new treatment strategies are urgently needed. Here, we report that a MuSK agonist antibody alleviates poly-PRinduced NMJ de fi cits in C9orf72-ALS mice. The HB9-PR F/F mice, which express poly-PR proteins in motor neurons, exhibited impaired motor behavior and NMJ de fi cits. 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 de fi cits, and extended the lifespan of C9orf72- ALS mice. Moreover, impaired NMJ transmission was observed in C9orf72-ALS patients. These fi ndings 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.