Novel therapeutic perspectives for sarcoglycanopathy: rescue of folding-defective mutants by means of protein folding correctors

Sarcoglycans (SG) are glycosylated proteins (α-, β-, γ- or δ-SG) forming a key structural complex, essential for the sarcolemma integrity of striated muscles during contraction. In sarcoglycanopathies, it is well known that defects in any one of the sarcoglycan genes lead to the strong reduction or even the loss of the SG-complex. Most of the reported cases are due to missense mutations originating a full length but folding-defective proteins. We proved that the primary pathological event in sarcoglycanopathy occurs in the Endoplasmic Reticulum, where the quality control system, by proof-reading newly synthesized sarcoglycans, recognizes and deliver to proteasomal degradation the folding-defective mutants. This results in secondary loss of the wild-type partners. We also demonstrated that many missense mutants retain their function as the entire complex can be properly rescued by reducing the mutant degradation. These findings opened new perspectives for therapy of this neglected disease allowing to design small molecule-based approaches aimed either to inhibit sarcoglycan mutants degradation, or to help their folding so that, skipping disposal, they can assemble and traffic at the proper site of action. We tested several small molecules known as CFTR correctors which were effective in recovering different mutants of alpha-sarcoglycan in cellular models and, notably, the whole SG-complex in primary myotubes from a patient suffering of α-sarcoglycanopathy. To confirm in vivo this successful strategy we need animal models expressing folding-defective sarcoglycans. As the SG-null mice are unsuitable to our purposes, and considering the large number of reported sarcoglycan missense mutants, our aim is now the generation and characterization of novel α-sarcoglycanopathy models by the transduction of the null mice with rAAVs (recombinant adeno associated viruses) expressing different missense mutants of the human α-SG. We are confident that, once fully characterized, these animals will become suitable sarcoglycanopathy models to test in vivo our therapeutic strategy.