Spinal muscular atrophy pathogenic mutations impair the axonogenic properties of axonal-survival of motor neuron

J. Neurochem. (2012) 121, 465–474. The axonal survival of motor neuron (a‐SMN) protein is a truncated isoform of SMN1, the spinal muscular atrophy (SMA) disease gene. a‐SMN is selectively localized in axons and endowed with remarkable axonogenic properties. At present, the role of a‐SMN in SMA is unknown. As a first step to verify a link between a‐SMN and SMA, we investigated by means of over‐expression experiments in neuroblastoma‐spinal cord hybrid cell line (NSC34) whether SMA pathogenic mutations located in the N‐terminal part of the protein affected a‐SMN function. We demonstrated here that either SMN1 missense mutations or small intragenic re‐arrangements located in the Tudor domain consistently altered the a‐SMN capability of inducing axonal elongation in vitro. Mutated human a‐SMN proteins determined in almost all NSC34 motor neurons the growth of short axons with prominent morphologic abnormalities. Our data indicate that the Tudor domain is critical in dictating a‐SMN function possibly because it is an association domain for proteins involved in axon growth. They also indicate that Tudor domain mutations are functionally relevant not only for FL‐SMN but also for a‐SMN, raising the possibility that also a‐SMN loss of function may contribute to the pathogenic steps leading to SMA. Mutated ha‐SMN proteins impair axonogenesis Axonal‐SMN is a truncated isoform of SMN1, the disease gene for spinal muscular atrophy or SMA. We demonstrated here that SMA pathogenic mutations affect a‐SMN function in stimulating axon growth. Mutated a‐SMN proteins induce the growth of shorter axons with prominent morphologic abnormalities. Our data represent the first indication possibly linking a‐SMN loss of function to SMA pathogenesis.