Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery
Open Access
- 5 March 2020
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 21 (5), 1813
- https://doi.org/10.3390/ijms21051813
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.Funding Information
- Fondazione Telethon (GEP12058, GGP15140)
- Muscular Dystrophy Association (577888)
This publication has 50 references indexed in Scilit:
- Correctors of the basic trafficking defect of the mutant F508del-CFTR that causes cystic fibrosisCurrent Opinion in Chemical Biology, 2013
- Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases: an in vitro study using cell linesOrphanet Journal of Rare Diseases, 2013
- Rescue of sarcoglycan mutations by inhibition of endoplasmic reticulum quality control is associated with minimal structural modificationsHuman Mutation, 2011
- Emergent Properties of Proteostasis in Managing Cystic FibrosisCold Spring Harbor Perspectives in Biology, 2010
- Sarcoglycanopathies: molecular pathogenesis and therapeutic prospectsExpert Reviews in Molecular Medicine, 2009
- Inhibition of Proteasome Activity Promotes the Correct Localization of Disease-Causing α-Sarcoglycan Mutants in HEK-293 Cells Constitutively Expressing β-, γ-, and δ-SarcoglycanThe American Journal of Pathology, 2008
- 4′-Methyl-4,5′-bithiazole-based correctors of defective ΔF508-CFTR cellular processingBioorganic & Medicinal Chemistry Letters, 2008
- Mannosidase I inhibition rescues the human α-sarcoglycan R77C recurrent mutationHuman Molecular Genetics, 2008
- Specific assembly pathway of sarcoglycans is dependent on beta‐ and delta‐sarcoglycanMuscle & Nerve, 2004
- Cadherin-like domains in α-dystroglycan, α/ε-sarcoglycan and yeast and bacterial proteinsCurrent Biology, 2002