CHARACTERIZATION AND FUNCTIONS OF THE SURVIVAL OF MOTOR NEURONS (SMN) COMPLEX

Spinal Muscular Atrophy (SMA) is a devastating neuromuscular disease characterized by the degeneration of the motor neurons of the spinal cord that leads to muscular atrophy. SMA is a common human genetic disease that affects 1 in every 10000 newborns and is the leading genetic cause of death of infants. No therapy is available to cure SMA. The gene responsible for SMA has been identified and named Survival of Motor Neurons (SMN). Since the identification of SMN as the SMA-determining gene, much research has focused on understanding the function of its product, the SMN protein. SMN is part of a large multiprotein complex that localizes both in the cytoplasm and in the nucleus and plays a role in the metabolism of cellular RNAs. All cells of an organism carry out complex biological processes such as cell division, development and differentiation through a series of events that ultimately rely on the correct execution of the gene expression program. RNA metabolism has a fundamental role in the process by which the genetic information stored in the DNA is utilized by all cells. Although SMA may arise from a defect in the functions of the SMN complex in the RNA metabolism of motor neurons, the precise molecular functions of SMN and the defects responsible for SMA are not yet known. Knowledge of the full spectrum of activities of the SMN complex at the molecular level is an essential step towards the goal of finding a therapy for SMA. The project aims at elucidating how the SMN complex enters the nucleus and characterizing its functions in transcription and processing of cellular RNAs. These studies will provide novel insights into the functions of SMN that may uncover the defects associated with SMA and be useful for developing assays for screening for SMA therapeutics.