DE PEDIATRIC COBRE: MECHANISMS OF CELL DEATH IN SPINAL MUSCULAR ATROPHY

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Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by degeneration of motor neurons and progressive muscle atrophy. The disease is one of the most common genetic causes of infant death. The gene responsible for SMA, survival motor neuron (SMN), exists in humans as two nearly identical copies (SMN1 and SMN2). Only deletion or mutation(s) of the telomeric copy of the gene (SMN1) causes the disease. The SMN protein has been known to function in assembly of the RNA splicing complex, however, Ithe mechanism(s) by which SMN-deficiency causes cell death in SMA are not clear. Our long-term goal is to lunderstand the mechanism(s) of motor neuron death in SMA and develop a means of prevention. SMN Iprotein has been reported to have some survival promoting functions in cultured cells. Our preliminary studies show that skin fibroblasts from SMA patients are more sensitive to certain death promoting stimuli than control fibroblasts. We hypothesize that the SMN protein is directly involved in cell survival and that toss of SMN's survival function results in motor neuron death in SMA. We will use fibroblasts from SMA patients, PC12 cells, and rat primary motor neuron cultures as model systems to test our hypothesis. We will determine the effect of expression of SMN protein in regulating cell death of SMA fibroblasts. We will further investigate the role of SMN in neuronal cell survival. Finally, we will determine biological pathway(s) of SMNmediated cell protection. Results from the proposed studies will provide insight into the mechanism(s) and signaling pathway(s) by which SMN protects cells from death and how a decrease in SMN function leads to the SMA phenotype. Ultimately, the obtained information could lead to develop therapeutic strategies to intervene.