Spinal muscular atrophy (SMA) is an autosomal recessive neurological disorder characterized by loss of lower motor neurons with resulting skeletal muscle atrophy, and is one of the leading genetic causes of infant death. SMA is a consequence of a deletion or other mutation of the survival of motor neuron-1 (SMN1) gene with preservation of the nearly identical SMN2 gene. The disease is associated with reduced levels of the SMN protein, which has the fundamental role of assembling small nuclear ribonucleoproteins-- molecules involved in pre-mRNA splicing (Battle et al, 2006; Lefebvre et al, 1995). In accordance with this function, loss of SMN leads to defects in splicing and affects the range of snRNAs and mRNAs produced in tissues (Gabanella et al, 2007; Zhang et al, 2008). While SMN's role in snRNP biogenesis has been well characterized, it remains uncertain why deletion of this ubiquitously expressed gene causes a progressive loss of motor neurons and a specific neuromuscular phenotype. Studying SMN protein stability may indicate how deficiencies in SMN cause disease. <br/> <br/> The over-arching aim of this dissertation is to characterize the degradation of the SMN protein. A detailed understanding of this mechanism could provide insight into methods for increasing levels of functional SMN protein as an approach to treatment of SMA. Our studies identified the ubiquitin proteasome system as a major degradative pathway for SMN. Steady-state SMN protein levels were increased in cells treated with proteasome inhibitors, but were unchanged when other degradative pathways were inhibited. This thesis examined the effect of proteasome inhibition on SMN protein levels and the SMA disease phenotype in vivo. Our results in SMA model mice highlighted a critical role for SMN in the central nervous system and showed that SMN increases in peripheral tissues could also improve the disease phenotype. We also identified and characterized a novel E3 ubiquitin ligase for SMN and showed that its targeted knockdown increased SMN in cell culture and ameliorated a neuromuscular defect in a C. elegans SMA model. Our work enhances the understanding of SMN protein degradation and demonstrates how this knowledge may be put to therapeutic use.
Kwon, Deborah YongHyun,
"Characterization of Survival Motor Neuron (SMN) Protein Degradation"
(2013).
Neuroscience Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.7301/Z0WH2N9Z
