Characterization of cellular pathways in spinal muscular atrophy

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Spinal Muscular Atrophy (SMA) is an autosomal recessive genetic disease, and is the leading genetic cause of death in infants. SMA is a severe neuromuscular disease characterized by loss of spinal [alpha]-motor neurons, resulting in the paralysis of skeletal muscle. SMA is caused by deficiency of Survival Motor Neuron (SMN) protein levels. Currently there is no effective treatment for SMA. The work presented in this thesis characterizes several potential SMA therapeutic targets. Follistatin is a natural antagonist of myostatin and over-expression of follistatin in mouse muscle leads to profound increases in skeletal muscle mass. To determine whether enhanced muscle mass impacts SMA, we administered recombinant follistatin to a SMA mouse model. Treated animals exhibited increased mass in several muscle groups, elevation in the number and cross-sectional area of ventral horn cells, gross motor function improvement, and mean lifespan extension by 30%, by preventing some of the early deaths, as compared to control animals. Reversing muscle atrophy associated with SMA may represent an unexploited therapeutic target for the treatment of SMA. The Wallerian degeneration slow (Wlds) gene is a spontaneous dominant mutation in mice that delays axon degeneration by approximately 2-3 weeks. We set out to examine the effect of Wlds on the phenotype of a mouse model of SMA. We found that Wlds does not alter the SMA phenotype, indicating that Wallerian degeneration does not directly contribute to the pathogenesis of SMA development.