Muscle Exosome-Derived miR-126 Regulates Local Synthesis of TDP-43 and NMJ Integrity in ALS

Amyotrophic lateral sclerosis (ALS) is characterized by neuromuscular junction (NMJ) disruption and neurodegeneration. Recent findings highlight a pivotal role for TDP-43 in forming axonal pathological condensates and facilitating NMJ disruption through inhibition of local protein synthesis. However, the mechanisms which drive local TDP-43 accumulation remain unknown. Here we identify TDP-43 axonal accumulation in peripheral nerves of SOD1 patients and mice stemming from its aberrant local synthesis. This is a non-cell-autonomous process driven by muscle-derived miR-126a-5p exosomes. Inhibiting muscle secretion of miR-126a-5p prompts pre-synaptic TDP-43 synthesis and accumulation that disrupts axonal translation and causes NMJ degeneration. Introducing miR-126 to SOD1G93A mice, primary co-cultures, and human iPSC-derived co-cultures with ALS mutations exhibits neuroprotective effects and delays motor decline. These findings identify a transcellular communication axis between muscles and motor neurons that regulates axonal local synthesis and NMJ maintenance offering insights into ALS onset and progression.