A Molecular Understanding of Why Alterations of SMN Give Rise to SMA

Project: Research project

Project Details


A Molecular Understanding of Why Alterations of SMN Give Rise to SMA A Molecular Understanding of Why Alterations of SMN Give Rise to SMA. Spinal muscular atrophy, SMA, is a leading cause of death in infancy. This disease is a neurodegenerative disease due to the loss of motor neurons with three clinic forms. For all three forms, this autosomal recessive disease arises due to changes in a gene identified as SMN1, or survival motor neuron 1. The gene encodes the protein SMN for which several functions have been identified and characterized. However, why SMA arises due to the genetic alterations of these functions is still not established. A critical reason for our limited understanding of the molecular cause of SMA is the lack of structural information for this protein. The three-dimensional structure has been determined for only a small portion of the protein called the Tudor domain. The sequence of SMN is not homologous to other proteins, aside from the Tudor domain region, and hence there is no structural basis for the development of molecular models for how the genetic changes alter the properties of SMN. To overcome this limitation, our overall goal is to develop a molecular understanding of the SMN protein. To achieve this goal, we plan to determine the three-dimensional structure of SMN using X-ray diffraction. For such studies crystals have already been obtained for three forms of SMN: SMN 14, the region of SMN encoded by exons 1-4; SMN WT, the entire SMN protein found in healthy patients, and SMN .7, the form of SMN predominately found in SMA patients. Analyses of these diffraction data are underway and a preliminary model has been obtained for SMN 14. Once the SMN 14 model is completed, the structures of SMN WT and SMN .7 will be determined. A variety of missense mutations have been identified in SMA patients. In order to understand how these mutations alter the properties of SMN we plan to determine the structural alterations that arise due to the mutations. Also, SMA may be associated with changes that occur in the interaction of SMN with other cellular components. To better understand these interactions, we propose to determine the structure of SMN with bound nucleic acids and SMN in complex with related proteins. At this point in time, there is no clinical treatment of motor neuron degeneration in SMA patients. The various approaches that are undergoing testing are largely based upon increasing the amount of SMN WT produced. The proposed studies should provide new insight into the function of SMN and how to compensate for alterations of SMN that are responsible for SMA. For example, a comparison of the structures of SMN WT and SMN .7 should reveal the key structural differences between these proteins and suggest molecules that could bind to the key structural regions of the SMN .7 protein and restore function. Thus, the molecular understanding of SMN resulting from the proposed studies should provide new directions for the development of molecular strategies for therapies that are protein-based and supplement the current gene-based approaches
Effective start/end date4/1/099/30/12


  • Families of SMA: $153,000.00


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