Molecular Etiology of Spinal Muscular Atrophy

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DESCRIPTION (provided by investigator): Spinal Muscular Atrophy (SMA) is a devastating neuromuscular disorder, caused by mutation of the human survival motor neuron 1 (SMN1) gene. Patients with SMA typically die early in childhood. Reduced levels of SMN protein cause the disease; complete loss of SMN expression results in prenatal lethality. The underlying cause of the SMA phenotype is not yet known. SMN protein is part of a large, oligomeric complex that plays an essential role in small nuclear ribonucleoprotein (snRNP) assembly, a process central to all eukaryotic cells. There is also evidence that SMN carries out additional tissue-specific functions in neurons and muscles. However, the molecular details of these tissue-specific functions of SMN are unclear. Thus learning more about SMN's role in neuromuscular development and function is essential for our understanding of SMA pathology. The major objective of this proposal is to obtain detailed knowledge of the role played by the SMN protein complex in the development and function of the neuromusculature, using Drosophila and mammalian model systems. To address this objective we have defined the following three Specific Aims: (1) We will assay the relative contributions of individual SMA-causing mutations on the general versus the tissue-specific functions of SMN in Drosophila. (2) We will identify the cellular and molecular mechanisms that lead to the observed muscle defects caused by reduced Drosophila SMN expression. (3) We will bring the findings from the first two Aims back into the mouse system through the use of specific transgenes and molecular assays. The combined data will elucidate the molecular, cellular and developmental biological consequences of reduced SMN expression and lead to a better understanding of the etiology of Spinal Muscular Atrophy. PUBLIC HEALTH RELEVANCE: Spinal Muscular Atrophy (SMA) is a common genetic disease that strikes one in 6,000-8,000 young children; most of whom die before reaching the age of two years. The responsible gene has been identified, but the precise role of the gene product is not known. To aid in the development of an effective treatment for SMA, this proposal seeks to understand the underlying basis of the disease.