A spinal muscular atrophy modifier implicates the SMN protein in SNARE complex assembly at neuromuscular synapses

Reduced survival motor neuron (SMN) protein triggers the motor neuron disease, spinal muscular atrophy (SMA). Restoring SMN prevents disease, but it is not known how neuromuscular function is preserved. We used model mice to map and identify an Hspa8G470R synaptic chaperone variant, which suppressed SMA. Expression of the variant in the severely affected mutant mice increased lifespan >10-fold, improved motor performance, and mitigated neuromuscular pathology. Mechanistically, Hspa8G470R altered SMN2 splicing and simultaneously stimulated formation of a tripartite chaperone complex, critical for synaptic homeostasis, by augmenting its interaction with other complex members. Concomitantly, synaptic vesicular SNARE com-plex formation, which relies on chaperone activity for sustained neuromuscular synaptic transmission, was found perturbed in SMA mice and patient-derived motor neurons and was restored in modified mutants. Identification of the Hspa8G470R SMA modifier implicates SMN in SNARE complex assembly and casts new light on how deficiency of the ubiquitous protein causes motor neuron disease.

Automated summary

Scientists have discovered a synaptic chaperone variant called Hspa8G470R that can suppress spinal muscular atrophy (SMA) and improve neuromuscular function in model mice. The variant alters SMN2 splicing and stimulates the formation of a tripartite chaperone complex critical for synaptic homeostasis. This study provides new insights into how deficiency of the SMN protein causes motor neuron disease.