Abstract
Sarcoglycanopathies are rare limb girdle muscular dystrophies, still incurable, even though symptomatic treatments may slow down the disease progression. Most of the disease-causing defects are missense mutations leading to a folding defective protein, promptly removed by the cell’s quality control, even if possibly functional. Recently, we repurposed small molecules screened for cystic fibrosis as potential therapeutics in sarcoglycanopathy. Indeed, cystic fibrosis transmembrane regulator (CFTR) correctors successfully recovered the defective sarcoglycan-complex in vitro. Our aim was to test the combined administration of some CFTR correctors with C17, the most effective on sarcoglycans identified so far, and evaluate the stability of the rescued sarcoglycan-complex. We treated differentiated myogenic cells from both sarcoglycanopathy and healthy donors, evaluating the global rescue and the sarcolemma localization of the mutated protein, by biotinylation assays and western blot analyses. We observed the additive/synergistic action of some compounds, gathering the first ideas on possible mechanism/s of action. Our data also suggest that a defective α-sarcoglycan is competent for assembly into the complex that, if helped in cell traffic, can successfully reach the sarcolemma. In conclusion, our results strengthen the idea that CFTR correctors, acting probably as proteostasis modulators, have the potential to progress as therapeutics for sarcoglycanopathies caused by missense mutations.
Highlights
LGMD2D (LGMD-R3 according to the new nomenclature [1]) is a rare autosomal recessive disease affecting striated muscle
Rescue of α-SG by cystic fibrosis transmembrane regulator (CFTR) Correctors in LGMD2D Myotubes In Carotti et al [19], we checked the ability of a few number of CFTR correctors in rescuing α-SG mutants in cell models
Corrector C17, was in depth analyzed for its efficacy in myogenic cells from a LGMD2D patient, a compound heterozygote for the L31P and V247M mutations on the SGCA alleles
Summary
LGMD2D (LGMD-R3 according to the new nomenclature [1]) is a rare autosomal recessive disease affecting striated muscle. An interesting point is the possibility to rescue the defective sarcoglycan as well as the entire SG-complex, by preventing the degradation of the mutant, acting either at the initial [15,16], intermediate [17] or final step [14] of the pathway. On these premises and taking advantage from the tremendous work done on another genetic disease, cystic fibrosis, that shares with sarcoglycanopathy a similar pathogenic mechanism [18], we elaborated a novel strategy of therapeutic intervention [19]. In the perspective of the development of a cure for sarcoglycanopathy, we evaluated the ability of the corrected α-SG mutant to interact with the wild type partners as well as the stability at the sarcolemma of the rescued complex
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