Targeting the ER Quality Control as a novel therapeutic approach for sarcoglycanopathy

Sarcoglycanopathy is a rare genetic disorder mainly affecting the proximal musculature. Defects in any one of the genes coding for α-, β-, δ- or γ-sarcoglycan (SG), four cell-membrane proteins forming an essential complex of striated muscle, lead to the sever reduction or even the loss of the entire SG-complex. Most of the sarcoglycanopathy cases are due to sarcoglycan missense mutations. We have proven that the primary pathological event occurs in the Endoplasmic Reticulum (ER) where the quality control system, by proof-reading newly synthesized sarcoglycans, recognizes and directs to degradation the folding-defective mutants, causing the secondary loss of the wild-type partners. We have also demonstrated that many of the missense mutants maintain their function and that the entire complex can be properly rescued by preventing the premature degradation of the mutants. This important knowledge allowed us to design two small molecule-based therapeutic strategies for sarcoglycanopathy aimed at either “saving” mutants from degradation or ”assisting” mutants in the ER folding process. The first approach is based on the pharmacological inhibition of the E3 ligase HRD1, key element of the sarcoglycan degradative route, that leads to the rescue of an α-SG mutant both in a cell model and in primary myotubes derived from a patient suffering of α-sarcoglycanopathy. Regarding the “protein assisting” strategy, we are testing several small molecules, known as protein-folding correctors, both in a cell model and in patient-derived myotubes. By helping α-SG mutants to reach a native/native-like conformation, these treatments allow the assembly of a functional complex that properly localizes at the plasma membrane. These results are the proof of principle for the development of novel pharmacological therapies for sarcoglycanopathy