SMA Investigator’s Research Highlighted in Science

Spinal muscular atrophy (SMA) is an inherited disease characterized by the selective death of motor neurons, resulting in generalized muscle weakness that is often fatal in infancy or early childhood. SMA is caused by deletions or mutations in the gene encoding survival motor neuron 1 protein (SMN1), whose function is unclear. SMN1 contributes to the assembly of the pre-mRNA splicing machinery, and loss of SMN1 has been hypothesized to cause disease through disruption of mRNA splicing. However, this cannot readily explain the selective effect of SMN1 loss on motor neurons.

An intriguing clue to this selectivity is provided by Setola et al., who identify a truncated form of SMN1 that arises from an alternative spliced SMN1 transcript that is preferentially expressed in the axonal projections of developing motor neurons. Forced expression of this SMN1 variant in cultured non-neuronal cells induces the formation of neurite-like extensions, a change in cell shape reminiscent of that occurring when motor neurons send out axons to their muscle targets. Whether this new variant of SMN1 affects axonal growth in vivo and plays a causal role in SMA remains to be investigated. — PAK