Unlocking ALS: Muscle Exosome Control TDP-43 Local Synthesis at the NMJced
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by TDP-43 mislocalization, aggregation, and disruption of neuromuscular junctions (NMJs). We have identified a key pathological mechanism involving the accumulation of TDP-43 in axons, which impairs local protein synthesis and drives NMJ degeneration. This process is linked to dysregulated muscle-derived exosomes carrying miR-126a-5p, essential for maintaining proper nerve-muscle communication. In ALS, reduced levels of miR-126a-5p lead to abnormal TDP-43 synthesis in axons. Restoring miR-126 in vivo and in human co-culture systems provides neuroprotection. Our findings highlight a transcellular signaling axis between muscles and neurons, offering new insights into NMJ maintenance and a potential foundation for ALS therapeutic strategies.