Ross, Jolill Erin

University of Missouri: MOspace

Public AbstractFirst Name:JolillMiddle Name:Last Name:RossAdviser's First Name:ChristianAdviser's Last Name:LorsonCo-Adviser's First Name:Co-Adviser's Last Name:Graduation Term:FS 2014Department:Microbiology- Medicine Degree:MSTitle:EXPLORING MODIFIERS IN SPINAL MUSCULAR ATROPHY: THE POWER OF AAV9Spinal Muscular Atrophy (SMA) is the second most common autosomal recessive disorder. The rate of newoccurring cases is 1 in 6,000, with a carrier frequency of 1 in 35. SMA is characterized by the loss ofSurvival Motor Neuron 1 (SMN1) gene, resulting in the degeneration of motor neurons located in the spinalcord, atrophy of muscles, paralysis, and eventually death. We utilize scAAV9, a viral vector, as a tool forintroducing heterogeneous genes as a method for delivery. We and others have shown that delivery of fulllength SMN1 to the “delta 7” SMA mouse model fully rescues the disease. Therefore, we employ scAAV9 tointroduce genes that are designed to modify the disease phenotype.  Furthermore, we will investigate whichdomains of SMN are important for its function with scAAV9. SMNrp1 is a putative paralogue to SMN; theTudor domain of SMNrp1 is highly similar to the Tudor domain of SMN. Both SMNrp1 and SMN areinvolved in spliceosome formation, therefore we hypothesized that SMNrp1 may be able to restore thefunction of SMN, making it a potential candidate as a modifier for SMA. Another example of a potentialmodifier of SMA is alpha-synuclein, which functions with synaptic vesicle recycling at the pre-synapticmembrane. Reduced alpha-synuclein protein and mRNA levels have been shown to correlate with reducedlevels of SMN protein. Therefore, we hypothesized that alpha-synuclein may work with SMN to stabilize andprotect motor neurons from SMA. Our results showed that SMNrp1 was unable to modify the SMAphenotype, while alpha-synuclein partially rescued the phenotype. In order to determine which functionaldomains within the SMN protein are particularly relevant for the development of SMA, we interrogated theability of phylogentically diverse SMN proteins to ameliorate the SMA phenotype in mice.  Phylogenticallymore distant species, such as Drosophila or S. pombe were hypothesized to be unable to restore SMNfunction, because of the reduced conservation of SMN protein domains. For this study, the severe SMN?7mouse model was utilized. We found that Smn from C. elegans, Drosophila, and S. pombe were not able torescue the phenotype of SMA mice. However zebrafish was able to rescue the phenotype and Xenopuspartially rescued the phenotype of SMA mice.  These studies will provide insight into the function of SMN aswell as provide evidence for potential therapeutics for SMA.

Exploring modifiers in spinal muscular atrophy : the power of AAV9

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