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Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, and is one of the leading genetic causes of infant death. It results from deletion /mutations of the survival motor neuron-1 (SMN1) gene, causing an SMN protein deficiency. SMA disease is characterized by the loss of lower motor neurons, and skeletal muscle weakness along with atrophy. Although there is currently no cure for the disease, increasing expression and decreasing degradation of SMN protein has been shown to rescue disease phenotype in animal models. SMN protein is degraded through the ubiquitin proteasome system (UPS), where the covalent attachment of ubiquitin to proteins marks them for degradation via the proteasome. Proteasome inhibition has previously been shown to increase SMN protein levels and ameliorate SMA disease phenotype in mice; however, a more specific target within the UPS pathway may prove to be more effective and less toxic. The selectivity of the ubiquitination process relies heavily on the interaction of the E3 ubiquitin-protein ligase with its specific substrate protein. In this study, we developed a cell-free assay to characterize Mib1 dependent ubiquitination of SMN. We concluded that Mib1 directly ubiquitinates SMN in a cell-free system. It was previously determined that Mib1 interacts with SMN at exon 6, consequently, SMN missing exon 6 is unable to bind Mib1. In support of this, our assay showed that SMN-myc was ubiquitinated more than SMNΔ6-myc. The assay we developed is now amenable for future high-throughput screens of candidate inhibitors for Mib1, and can be repeated with modifications of SMN and Mib1 in order to better characterize Mib1 dependent SMN ubiquitination.

Last Modified December 14, 2012