Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery
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 qualit...
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doaj-1296b28e0b70450795dd8904e33285172020-11-25T03:00:20ZengMDPI AGInternational Journal of Molecular Sciences1422-00672020-03-01215181310.3390/ijms21051813ijms21051813Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex RecoveryMarcello Carotti0Martina Scano1Irene Fancello2Isabelle Richard3Giovanni Risato4Mona Bensalah5Michela Soardi6Dorianna Sandonà7Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/b 35131 Padova, ItalyDepartment of Biomedical Sciences, University of Padova, Via U. Bassi 58/b 35131 Padova, ItalyDepartment of Biomedical Sciences, University of Padova, Via U. Bassi 58/b 35131 Padova, ItalyGénéthon INSERM, U951, INTEGRARE Research Unit, Univ Evry, Université Paris-Saclay, 91002 Evry, FranceDepartment of Biomedical Sciences, University of Padova, Via U. Bassi 58/b 35131 Padova, ItalyINSERM, Institut de Myologie, U974, Center for Research in Myology, Sorbonne Université, 75013 Paris, FranceDepartment of Biomedical Sciences, University of Padova, Via U. Bassi 58/b 35131 Padova, ItalyDepartment of Biomedical Sciences, University of Padova, Via U. Bassi 58/b 35131 Padova, ItalySarcoglycanopathies 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.https://www.mdpi.com/1422-0067/21/5/1813sarcoglycanopathymyogenic cellsmyotubesfolding-defective proteinsprotein folding correctorscftr correctorsproteostasis regulators |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marcello Carotti Martina Scano Irene Fancello Isabelle Richard Giovanni Risato Mona Bensalah Michela Soardi Dorianna Sandonà |
spellingShingle |
Marcello Carotti Martina Scano Irene Fancello Isabelle Richard Giovanni Risato Mona Bensalah Michela Soardi Dorianna Sandonà Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery International Journal of Molecular Sciences sarcoglycanopathy myogenic cells myotubes folding-defective proteins protein folding correctors cftr correctors proteostasis regulators |
author_facet |
Marcello Carotti Martina Scano Irene Fancello Isabelle Richard Giovanni Risato Mona Bensalah Michela Soardi Dorianna Sandonà |
author_sort |
Marcello Carotti |
title |
Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery |
title_short |
Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery |
title_full |
Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery |
title_fullStr |
Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery |
title_full_unstemmed |
Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery |
title_sort |
combined use of cftr correctors in lgmd2d myotubes improves sarcoglycan complex recovery |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2020-03-01 |
description |
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. |
topic |
sarcoglycanopathy myogenic cells myotubes folding-defective proteins protein folding correctors cftr correctors proteostasis regulators |
url |
https://www.mdpi.com/1422-0067/21/5/1813 |
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