ROLE OF SARCOSPAN IN CELL SURFACE EXPRESSION OF LAMININ-BINDING COMPLEXES

University Of California Los Angeles, Los Angeles CA

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY/ABSTRACT Duchenne muscular dystrophy (DMD) is a debilitating genetic disorder that causes progressive muscle weakness, ultimately leading to death in affected teenagers and young adults. At present, there are no specific therapies for DMD and treatment options are limited to supportive care. DMD is caused by mutations in dystrophin, a component of the dystrophin-glycoprotein complex (DGC). Along with the utrophin-glycoprotein complex (UGC) and the ?7?1 integrin complex, the DGC is one of 3 major muscle adhesion complexes that link the extracellular matrix to the intracellular actin cytoskeleton. In DMD, the absence of dystrophin and subsequent loss of the DGC leaves the sarcolemma highly vulnerable to contraction-induced damage, ultimately leading to muscle fiber degeneration and death. Previous work from our lab has shown that a small transmembrane protein called sarcospan can enhance the recruitment of adhesion complex proteins to the cell surface. This increase in adhesion complex abundance improves muscle membrane stability in dystrophin-null animals, preventing many of the dystrophic changes associated with DMD. These findings lead us to hypothesize that sarcospan acts as a chaperone-like molecule during the trafficking of adhesion complexes to the cell surface. In this proposal, I will examine the role of sarcospan in the maturation and assembly of adhesion complexes within muscle endomembrane compartments. I will additionally test whether sarcospan can be used to boost the efficacy of exon-skipping therapy, a class of therapeutics currently in clinical trials. The results from these studies will illuminate a largely unexplored aspect of muscle biology, and provide important insight into the translational potential of sarcospan as a therapeutic target in DMD.