SMA model mice as tools to understand human Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a common, frequently fatal neuromuscular disease caused by recessively inherited mutations in the SMN1 gene and, consequently, a paucity of its translated protein product, SMN.  SMA is the most commonly inherited cause of infant mortality.  As of yet there is no treatment for the disease.  To gain a better understanding of the human disease, we have modeled SMA in mice.  Our studies demonstrate that reduced SMN has a novel, previously unappreciated detrimental effect on the distal end of the motor unit.  These defects which localize to the neuromuscular junctions (NMJs) are characterized by an impaired maturation of the acetylcholine receptor clusters suggesting that SMN may have a role in the formation and/or maintenance of the neuromuscular synapse.  We have extended these studies to define the cellular site of action of the SMN protein and demonstrated that restoring protein to target tissues of the disease following onset of the phenotype is nevertheless capable of remarkable phenotypic rescue.  These results have important implications for motor neuron biology as well as for future SMA therapies.