Defining the anti-apoptotic function of the survival of motor neuron (SMN) protein and assessment of a novel therapy for the treatment of spinal muscular atrophy (SMA)

Spinal muscular atrophy (SMA) is a neurodegenerative disorder primarily affecting motor neurons. This untreatable disease is caused by the absence of a functional survival of motor neuron 1 (SMN1) gene, which leads to a critical reduction in fulllength survival of motor neuron (SMN) protein. The multifunctional SMN protein is important in the biogenesis of small nuclear ribonuclear proteins, pre-mRNA splicing and motor neuron viability. However, the precise functions of the SMN protein in promoting neuronal survival are yet to be completely understood. To this end, the aims of this project were to elucidate the pro-survival role(s) of the SMN protein and assess a novel therapeutic approach for the delivery of recombinant SMN protein into cells. Therefore, the hypotheses of this project stated that the SMN protein plays an important role in regulating apoptosis, and successful delivery of the SMN protein to cells can be achieved using a cell-penetrating peptide (CPP). To elucidate the pro-survival functions of the SMN protein, a novel in vitro apoptotic cell death model was established. Using differentiated human SH-SY5Y neuroblastoma cells, a predominately apoptotic cell death was induced through the inhibition of the PI3-kinase/Akt survival pathway. Results from these experiments revealed that SMN over-expression protected SH-SY5Y cells from a caspase-dependent apoptotic cell death. Further, SMN over-expression blocked calpain-mediated activation and cleavage of the caspase-3 protein. The demonstration of this previously unknown mechanism has identified a pathway activated by the SMN to block apoptosis.