AXONAL SURVIVAL MOTOR NEURON PROTEIN (a-SMN): ROLE IN THE PATHOGENESIS OF SPINAL MUSCULAR ATROPHY (SMA) AND IN THE MECHANISMS OF AXONOGENESIS
- 2 Years 2008/2010
- 232.400€ Total Award
Spinal muscular atrophy or SMA is a severe genetically determined disease characterized by selective degeneration of spinal cord motor neurons and primarily affecting childhood. The clinical picture of SMA is a progressive paralysis involving all skeletal muscles and leading in more severe cases to respiratory insufficiency and death. SMA is one of the leading genetic causes of infant mortality, affecting about one child in 6000 live births. In spite of the identification in 1995 of the Survival Motor Neuron (SMN) gene as the disease gene, the pathogenesis of SMA is still obscure, and no effective therapy is available. Our group has recently identified a novel isoform of the SMN protein, called a-SMN (for axonal SMN). a-SMN is down-regulated during spinal cord development and selectively expressed in the axons of motor neurons. In addition, if over-expressed in cultured motor neurons, it stimulates axonogenesis in a time-dependent fashion. Since a-SMN is preferentially encoded by the SMN1 gene, the disease gene of SMA, we hypothesize that a-SMN may play a relevant role in the pathogenesis of the human disease. On this basis, we aim at gathering more direct data on the involvement of a-SMN in SMA and obtaining deeper insights on the functions played by a-SMN in inducing axon growth in motor neurons. To obtain these goals, we propose to: A) verify the expression of a-SMN in SMA patients; B) analyze the effect of SMN1 mutations on the a-SMN function; C) develop strategies to reduce a-SMN expression in cell cultures; D) develop in vitro models of a-SMN expression; E) define genes and proteins functionally involved in the a-SMN-dependent process of axonogenesis. We believe that our research project is likely to contribute novel insight into the pathogenesis of SMA, and that this step is the essential prerequisite for the development of novel and effective therapeutic strategies for this devastating disease.