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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 quality control,...

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Autores principales: Carotti, Marcello, Scano, Martina, Fancello, Irene, Richard, Isabelle, Risato, Giovanni, Bensalah, Mona, Soardi, Michela, Sandonà, Dorianna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084537/
https://www.ncbi.nlm.nih.gov/pubmed/32155735
http://dx.doi.org/10.3390/ijms21051813
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author Carotti, Marcello
Scano, Martina
Fancello, Irene
Richard, Isabelle
Risato, Giovanni
Bensalah, Mona
Soardi, Michela
Sandonà, Dorianna
author_facet Carotti, Marcello
Scano, Martina
Fancello, Irene
Richard, Isabelle
Risato, Giovanni
Bensalah, Mona
Soardi, Michela
Sandonà, Dorianna
author_sort Carotti, Marcello
collection PubMed
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.
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spelling pubmed-70845372020-03-24 Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery Carotti, Marcello Scano, Martina Fancello, Irene Richard, Isabelle Risato, Giovanni Bensalah, Mona Soardi, Michela Sandonà, Dorianna Int J Mol Sci Article 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. MDPI 2020-03-06 /pmc/articles/PMC7084537/ /pubmed/32155735 http://dx.doi.org/10.3390/ijms21051813 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Carotti, Marcello
Scano, Martina
Fancello, Irene
Richard, Isabelle
Risato, Giovanni
Bensalah, Mona
Soardi, Michela
Sandonà, Dorianna
Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084537/
https://www.ncbi.nlm.nih.gov/pubmed/32155735
http://dx.doi.org/10.3390/ijms21051813
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