Molecular Pathway Regulating the Stability of β-Dystroglycan – SH3BP2-DG

The proper functioning of muscles is essential for performing everyday life activities such as eating, speaking, and breathing. The integrity of the sarcolemma (muscle membrane) is maintained by the dystrophin-associated glycoprotein complex (DGC). The functioning of the DGC is impaired in many muscular dystrophies. For example, the absence of dystrophin, caused by mutations in its encoding gene, is the primary cause of Duchenne muscular dystrophy (DMD). Currently, there is no cure for DMD, and treatment focuses only on alleviating symptoms. Numerous clinical trials on DMD are ongoing, most of which concentrate on restoring dystrophin production in muscles.

Importantly, the absence of dystrophin leads to the degradation of β-dystroglycan (β-DG), a protein that links the extracellular matrix to the actin cytoskeleton. This occurs because, in the absence of dystrophin, the PPXY motif on β-DG becomes exposed and undergoes phosphorylation, resulting in β-DG degradation. Despite decades of research on DMD, little is known about the proteins that regulate β-DG stabilization on the cell surface.

Our research aims to identify new proteins that interact with the PPXY motif of β-DG and stabilize β-DG by preventing its phosphorylation. Additionally, we will investigate the intracellular trafficking pathways of β-DG during its degradation. We will also explore the therapeutic potential of the newly discovered proteins for treating DMD and potentially other types of muscular dystrophies.

The results of our studies may have significant clinical applications in understanding and developing new strategies for treating muscular dystrophies.