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Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation

Limb-girdle muscular dystrophy type 2D (LGMD2D) is characterized by a progressive proximal muscle weakness. LGMD2D is caused by mutations in the gene encoding α-sarcoglycan (α-SG), a dystrophin-associated glycoprotein that plays a key role in the maintenance of sarcolemma integrity in striated muscl...

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Autores principales: Hoch, Lucile, Henriques, Sara F., Bruge, Celine, Marsolier, Justine, Benabides, Manon, Bourg, Nathalie, Tournois, Johana, Mahé, Gurvan, Morizur, Lise, Jarrige, Margot, Bigot, Anne, Richard, Isabelle, Nissan, Xavier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502821/
https://www.ncbi.nlm.nih.gov/pubmed/31061434
http://dx.doi.org/10.1038/s41598-019-43399-w
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author Hoch, Lucile
Henriques, Sara F.
Bruge, Celine
Marsolier, Justine
Benabides, Manon
Bourg, Nathalie
Tournois, Johana
Mahé, Gurvan
Morizur, Lise
Jarrige, Margot
Bigot, Anne
Richard, Isabelle
Nissan, Xavier
author_facet Hoch, Lucile
Henriques, Sara F.
Bruge, Celine
Marsolier, Justine
Benabides, Manon
Bourg, Nathalie
Tournois, Johana
Mahé, Gurvan
Morizur, Lise
Jarrige, Margot
Bigot, Anne
Richard, Isabelle
Nissan, Xavier
author_sort Hoch, Lucile
collection PubMed
description Limb-girdle muscular dystrophy type 2D (LGMD2D) is characterized by a progressive proximal muscle weakness. LGMD2D is caused by mutations in the gene encoding α-sarcoglycan (α-SG), a dystrophin-associated glycoprotein that plays a key role in the maintenance of sarcolemma integrity in striated muscles. We report here on the development of a new in vitro high-throughput screening assay that allows the monitoring of the proper localization of the most prevalent mutant form of α-SG (R77C substitution). Using this assay, we screened a library of 2560 FDA-approved drugs and bioactive compounds and identified thiostrepton, a cyclic antibiotic, as a potential drug to repurpose for LGMD2D treatment. Characterization of the thiostrepton effect revealed a positive impact on R77C-α-SG and other missense mutant protein localization (R34H, I124T, V247M) in fibroblasts overexpressing these proteins. Finally, further investigations of the molecular mechanisms of action of the compound revealed an inhibition of the chymotrypsin-like activity of the proteasome 24 h after thiostrepton treatment and a synergistic effect with bortezomib, an FDA-approved proteasome inhibitor. This study reports on the first in vitro model for LGMD2D that is compatible with high-throughput screening and proposes a new therapeutic option for LGMD2D caused by missense mutations of α-SG.
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spelling pubmed-65028212019-05-20 Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation Hoch, Lucile Henriques, Sara F. Bruge, Celine Marsolier, Justine Benabides, Manon Bourg, Nathalie Tournois, Johana Mahé, Gurvan Morizur, Lise Jarrige, Margot Bigot, Anne Richard, Isabelle Nissan, Xavier Sci Rep Article Limb-girdle muscular dystrophy type 2D (LGMD2D) is characterized by a progressive proximal muscle weakness. LGMD2D is caused by mutations in the gene encoding α-sarcoglycan (α-SG), a dystrophin-associated glycoprotein that plays a key role in the maintenance of sarcolemma integrity in striated muscles. We report here on the development of a new in vitro high-throughput screening assay that allows the monitoring of the proper localization of the most prevalent mutant form of α-SG (R77C substitution). Using this assay, we screened a library of 2560 FDA-approved drugs and bioactive compounds and identified thiostrepton, a cyclic antibiotic, as a potential drug to repurpose for LGMD2D treatment. Characterization of the thiostrepton effect revealed a positive impact on R77C-α-SG and other missense mutant protein localization (R34H, I124T, V247M) in fibroblasts overexpressing these proteins. Finally, further investigations of the molecular mechanisms of action of the compound revealed an inhibition of the chymotrypsin-like activity of the proteasome 24 h after thiostrepton treatment and a synergistic effect with bortezomib, an FDA-approved proteasome inhibitor. This study reports on the first in vitro model for LGMD2D that is compatible with high-throughput screening and proposes a new therapeutic option for LGMD2D caused by missense mutations of α-SG. Nature Publishing Group UK 2019-05-06 /pmc/articles/PMC6502821/ /pubmed/31061434 http://dx.doi.org/10.1038/s41598-019-43399-w Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hoch, Lucile
Henriques, Sara F.
Bruge, Celine
Marsolier, Justine
Benabides, Manon
Bourg, Nathalie
Tournois, Johana
Mahé, Gurvan
Morizur, Lise
Jarrige, Margot
Bigot, Anne
Richard, Isabelle
Nissan, Xavier
Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation
title Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation
title_full Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation
title_fullStr Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation
title_full_unstemmed Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation
title_short Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation
title_sort identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502821/
https://www.ncbi.nlm.nih.gov/pubmed/31061434
http://dx.doi.org/10.1038/s41598-019-43399-w
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