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Open AccessArticle

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

1
Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/b 35131 Padova, Italy
2
Généthon INSERM, U951, INTEGRARE Research Unit, Univ Evry, Université Paris-Saclay, 91002 Evry, France
3
INSERM, Institut de Myologie, U974, Center for Research in Myology, Sorbonne Université, 75013 Paris, France
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(5), 1813; https://doi.org/10.3390/ijms21051813
Received: 13 February 2020 / Accepted: 28 February 2020 / Published: 6 March 2020
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
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. View Full-Text
Keywords: sarcoglycanopathy; myogenic cells; myotubes; folding-defective proteins; protein folding correctors; CFTR correctors; proteostasis regulators sarcoglycanopathy; myogenic cells; myotubes; folding-defective proteins; protein folding correctors; CFTR correctors; proteostasis regulators
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MDPI and ACS Style

Carotti, M.; Scano, M.; Fancello, I.; Richard, I.; Risato, G.; Bensalah, M.; Soardi, M.; Sandonà, D. Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery. Int. J. Mol. Sci. 2020, 21, 1813. https://doi.org/10.3390/ijms21051813

AMA Style

Carotti M, Scano M, Fancello I, Richard I, Risato G, Bensalah M, Soardi M, Sandonà D. Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery. International Journal of Molecular Sciences. 2020; 21(5):1813. https://doi.org/10.3390/ijms21051813

Chicago/Turabian Style

Carotti, Marcello; Scano, Martina; Fancello, Irene; Richard, Isabelle; Risato, Giovanni; Bensalah, Mona; Soardi, Michela; Sandonà, Dorianna. 2020. "Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery" Int. J. Mol. Sci. 21, no. 5: 1813. https://doi.org/10.3390/ijms21051813

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