Novel compounds induce AChR clustering and improve motor function in myasthenia gravis animal models.

The neuromuscular junction (NMJ), the synapse between motor nerves and skeletal muscles, is implicated in the pathogenesis of various neuromuscular disorders, including myasthenia gravis (MG), congenital myasthenia, and amyotrophic lateral sclerosis. Postsynaptic clustering of acetylcholine receptors (AChRs) is crucial for NMJ formation. This process is initiated by agrin, a glycoprotein secreted from motor nerve terminals, which activates muscle-specific tyrosine kinase (MuSK) via its coreceptor, low-density lipoprotein receptor-related protein 4 (Lrp4), and thereby activates downstream signaling pathways that induce AChR clustering. MG is an autoimmune disease characterized by the production of autoantibodies against NMJ components such as AChR, MuSK, and Lrp4, which leads to impaired neuromuscular transmission and motor dysfunction. In this study, we identified orally active small-molecule compounds that promote AChR clustering through the Lrp4-MuSK signaling axis. Knockdown experiments demonstrated that Lrp4 was responsible for the compounds to induce AChR clustering. The compounds induced MuSK phosphorylation following the compound treatment in C2C12 cells and improved motor function and increased muscle volume in both MuSK-MG mice and AChR-MG rat models. Together, these findings identify orally active small molecules that potentiate Lrp4-MuSK signaling and highlight a pharmacological strategy to modulate NMJ function for MG and related neuromuscular disorders.