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Series GSE119841 Query DataSets for GSE119841
Status Public on Sep 19, 2019
Title Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Limb-girdle muscular dystrophies type 2D (LGMD2D) are characterized by a progressive proximal muscle weakness. LGMD2D is due to mutations in the gene encoding α sarcoglycan (-SG), a dystrophin-associated glycoprotein playing a key role in the maintenance of sarcolemma integrity in striated muscles. Here, we report the development of a new in vitro high-throughput screening assay that allows monitoring the proper localization of the most prevalent mutant form of -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 thiostrepton effect revealed a positive impact on R77C--SG and other missense mutant proteins (R34H, I124T, V247M) localization 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 24h following thiostrepton treatment and a synergic effect with bortezomib, a FDA-approved proteasome inhibitor. This study reports the first in vitro model of LGMD2D compatible with high throughput screening and propose a new therapeutical option for LGMD2D caused by missense mutations of -SG.
Overall design Identification of Thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation
Citation(s) 34278269
Submission date Sep 12, 2018
Last update date Jul 20, 2021
Phone +33169908529
Organization name I-Stem/INSERM U861
Street address 28, Rue Henri Desbruères
City Corbeil-Essonnes
ZIP/Postal code 91100
Country France
Platforms (1)
GPL17303 Ion Torrent Proton (Homo sapiens)
Samples (12)
GSM3384933 Fibroblasts-R77C-alpha-SGmCh-DMSO 0,1% n1
GSM3384934 Fibroblasts-R77C-alpha-SGmCh-DMSO 0,1% n2
GSM3384935 Fibroblasts-R77C-alpha-SGmCh-DMSO 0,1% n3
BioProject PRJNA490439
SRA SRP161622

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Supplementary file Size Download File type/resource
GSE119841_L.Hoch_and_al_2018-normalized_gene_abundance_measurements_RPM.txt.gz 747.4 Kb (ftp)(http) TXT
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