Protein-stabilizing and neurotransmission-potentiating activities of a synaptic chaperone modify spinal muscular...

Spinal muscular atrophy (SMA) is an oft-fatal infantile-onset neuromuscular disease caused by low SMN protein. Administration of SMN-inducing agents to SMA newborns prevents early mortality, but therapeutic outcomes vary considerably, and disease mechanisms remain poorly understood. Genetic modifiers can provide clues to disease mechanisms and serve as targets for novel treatments. Here, we describe how one such modifier suppresses SMA in model mice. We show that the modifier, an Hspa8 ^G470R synaptic chaperone variant we previously identified, functions beyond an already defined role as an SMN2 splice-switcher. Even in mice lacking the SMN2 gene, the modifier, whether expressed genetically or exogenously, potently suppressed disease, preventing motor neuron degeneration, ameliorating neuromuscular dysfunction and extending lifespan more than ten-fold. Unexpectedly, this was once again associated with incremental SMN increase - an outcome we discovered is linked to Hspa8 ^G470R -mediated autophagy, effects of the modifier on autophagy-associated intermediate complexes and, ultimately, reduced SMN turnover. Interestingly, however, Hspa8 ^G470R also stimulated neuromuscular transmission significantly, raising the effective, functional readily releasable pool of motor neuronal synaptic vesicles. This effect was not limited to mutants alone but apparent in healthy controls too and did not correlate with mere increase in SMN. Combined, these outcomes suggest that Hspa8 governs neuromuscular function in several ways including direct effects on synapses. Mechanisms revealed here shed additional light on pathways gone awry in SMA - ones that might be modulated to develop or refine therapies for neuromuscular disorders at large.