Multiple spinal muscular atrophy disease-modifying effects of a Hspa8G470R synaptic chaperone variant

Spinal muscular atrophy (SMA) is an oft-fatal infantile-onset neuromuscular disease caused by homozygous loss of the Survival of Motor Neuron 1 (SMN1) gene and, consequently, 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, an Hspa8G470R synaptic chaperone variant we identified, suppresses SMA in model mice. Our results highlight two distinct mechanisms of action of the variant chaperone. First, it raises SMN incrementally, an outcome we discovered is not linked to a previously identified splice modulating function of the modifier but instead to Hspa8G470R-mediated autophagy, effects of the variant on autophagy-associated intermediate complexes and, ultimately, reduced SMN turnover. Interestingly, however, the modifier also stimulated neuromuscular transmission significantly, raising the effective, functional readily releasable pool of motor neuronal synaptic vesicles. Notably, this second outcome was not limited to mutants alone but discernible in healthy controls too, appearing independent of SMN levels and thus indicative of a distinct disease-modifying effect of the chaperone variant that operates specifically at neuromuscular synapses. Combined, the two mechanisms of Hspa8G470R action identified here suppressed the SMA phenotype potently, preventing spinal motor neuron degeneration, ameliorating neuromuscular dysfunction and extending lifespan in model mice more than ten-fold. Results presented in this study shed additional light on pathways gone awry in SMA - ones that might be modulated to develop or refine therapies for neuromuscular disorders at large.