Mutations or deletions in the survival of motor neuron 1 (SMN1) gene that decreases the SMN protein expression result in spinal muscular atrophy (SMA), a genetically inherited disease that causes progressive muscle degeneration and infant deaths. Functionally, SMN forms a complex with other proteins including Gemins 2-8 and Unrip. The SMN complex is essential for the biogenesis of spliceosomal nuclear ribonucleoproteins and it is involved in translocation of beta-actin to axonal growth cones. Currently, it is unclear how loss of SMN function leads to selective motor-neuron cell death. Animal models have demonstrated that increase of the SMN protein level can rescue the disease phenotype, suggesting that stabilization of the SMN protein is an extremely promising strategy for SMA treatment. In this study, we will employ biochemical, cell biological and next- generation genomic sequencing techniques to determine mechanisms by which the SMN complex assembly, stability and functions are regulated by SMN ubiquitination/deubiquitination. Our study might discover a deubiquitinating enzyme as a novel regulator of the SMN complex and thus, identify a novel therapeutic target for SMA.

Public Health Relevance

Spinal muscular atrophy (SMA) is the second most common autosomal recessive genetic disease in humans and the leading cause of genetically linked infant mortality. SMA is characterized by muscle weakness and atrophy from progressive motor neuron degeneration. In general, the severity of SMA correlates well with levels of the SMN protein in patient cells. Thus, discovery of novel modulators that can increase the protein levels of SMN will definitely identify new therapeutic targets for SMA. In this study, we will investigate how a SMN-interacting protein functions to stabilize the SMN protein.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Membrane Biology and Protein Processing (MBPP)
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Porter, John D
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University of Colorado Denver
Schools of Medicine
United States
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