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

ABSTRACT: 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 Hspa8^G470R 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, Hspa8^G470R 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 complex formation, which relies on chaperone activity f

SUBMITTER: Kim JK 

PROVIDER: S-EPMC10164130 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature