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. Here, AGRN is linked to proximal spinal muscular atrophy.