Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery.

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ID: 100637
2020
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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.
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carotti2020combinedinternational Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Carotti, Marcello;Scano, Martina;Fancello, Irene;Richard, Isabelle;Risato, Giovanni;Bensalah, Mona;Soardi, Michela;Sandonà, Dorianna;
Journal International journal of molecular sciences
Year 2020
DOI
E1813
URL
Keywords
cftr correctors folding-defective proteins myogenic cells myotubes protein folding correctors proteostasis regulators sarcoglycanopathy

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