Neuromuscular junction pathology in amyotrophic lateral sclerosis and emerging molecular therapeutic strategies

Traditionally conceptualized as a soma-centric pathology, amyotrophic lateral sclerosis (ALS) is a fatal, heterogeneous neurodegenerative disease. The suboptimal outcomes of central nervous system (CNS)-directed therapeutic strategies have necessitated a shift in focus toward the dying-back hypothesis. This hypothesis contends that synaptic disconnection and axonal retraction at the distal neuromuscular junction (NMJ) are early pathological events that may antedate overt motor neuron loss. This review systematically examines the NMJ as an early vulnerable and therapeutically tractable peripheral niche in ALS pathogenesis, rather than merely a downstream consequence of proximal proteinopathy. Evidence from human clinical samples and ALS mouse models, particularly SOD1-G93A mice, collectively supports the early vulnerability of the NMJ, with the temporal precedence of denervation, synaptic retraction, and mitochondrial dysfunction most clearly demonstrated in experimental models. We highlight how the breakdown of the tripartite synapse-comprising the motor terminal, skeletal muscle, and terminal Schwann cells (tSCs)-may disrupt essential neurotrophic signaling and local metabolic homeostasis. Furthermore, we discuss how advancements in humanized in vitro NMJ models and spatial transcriptomics provide unprecedented resolution into localized RNA dysmetabolism and bioenergetic failure. Finally, we evaluate emerging therapeutic strategies specifically designed to stabilize or restore the NMJ, including MuSK agonists and other NMJ-directed approaches. By recontextualizing the NMJ as a critical early site of vulnerability, we propose that targeting the peripheral synaptic microenvironment may offer a promising strategy for modifying the progression of ALS.