Rescue of folding-defective alpha-sarcoglycan mutants by means of protein folding correctors

Sarcoglycans (SG) are glycosylated proteins (alpha-, beta-, delta- or gamma-SG) forming a key structural complex, essential for the sarcolemma integrity of striated muscles during contraction. It is well known that defects in any one of the genes coding for sarcoglycans lead to the severe reduction or even the complete loss of SG-complex. Most of the mutations associated to sarcoglycanopathy are missense mutations and the disease severity is strictly related to the residual amount of sarcoglycans found at sarcolemma. We have recently proven that the primary event in these cases is the premature degradation of a folding-defective sarcoglycan, followed by the secondary loss of the wild-type partners, operated by the Endoplasmic Reticulum-Associated Degradation. We have also demonstrated that many missense mutants retain their function and that the entire complex can be properly rescued by targeting the degradative pathway. The knowledge of the pathogenic mechanism of sarcoglycanopathy has been also essential to design novel therapeutic strategies for this neglected and still incurable disease. These strategies intend not only to merely inhibit degradation of sarcoglycan mutants, but particularly to help their folding so that, structurally stabilized, mutants can skip disposal and traffic at the proper site of action. We tested several protein folding correctors, screened for the treatment of cystic fibrosis and called CFTR correctors. These small molecules were effective in recovering different mutants of alpha-sarcoglycan in cellular models, and notably in primary myotubes from a patient suffering of alpha-sarcoglycanopathy. In the latter case, the whole sarcoglycan complex was properly rescued at the plasma membrane, suggesting that a sort of “protein repair strategy” can be adopted to treat sarcoglycanopathy. Although the mechanism by which CFTR correctors act on sarcoglycan mutants need to be clarified, these data represent the proof o principle of a novel pharmacological strategy aiming at correcting mutant folding by using well-known and available small molecules.