Here we evaluated the role of agrin/neurotrypsin system in a murine model of SMA: we observed that interference with this system via injection of the neurotrypsin-resistant agrin fragment NT-1645 exerted beneficial effects on muscle trophism and NMJ maturation, restoring the crosstalk between muscles and MNs and improving motor performance and extending survival. The gene discussed is PRSS12; the disease is proximal spinal muscular atrophy.