Identification of therapeutics that target eEF1A2 and upregulate utrophin A translation in dystrophic muscles
| Autor: | Alan J. Mears, Jean-Marc Renaud, Jason R. Vanstone, Nadine J. Adam, Christine Péladeau, Adele Coriati, Hasanen Al-Rewashdy, Bernard J. Jasmin, Mohamed Thabet, Lucas Bronicki, Martin Holcik |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Utrophin Duchenne muscular dystrophy animal diseases Science Drug Evaluation Preclinical General Physics and Astronomy EEF1A2 030105 genetics & heredity Biology Internal Ribosome Entry Sites General Biochemistry Genetics and Molecular Biology Article Cell Line Myoblasts 03 medical and health sciences Mice Peptide Elongation Factor 1 Downregulation and upregulation medicine Myocyte Animals Humans Muscular dystrophy lcsh:Science Pravastatin Mice Knockout Multidisciplinary Drug Repositioning Translation (biology) General Chemistry Neuromuscular disease medicine.disease musculoskeletal system Phenotype 3. Good health Cell biology Betaxolol Up-Regulation Muscular Dystrophy Duchenne Disease Models Animal 030104 developmental biology Drug screening Protein Biosynthesis Mice Inbred mdx lcsh:Q 5' Untranslated Regions |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Up-regulation of utrophin in muscles represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy. We previously demonstrated that eEF1A2 associates with the 5’UTR of utrophin A to promote IRES-dependent translation. Here, we examine whether eEF1A2 directly regulates utrophin A expression and identify via an ELISA-based high-throughput screen, FDA-approved drugs that upregulate both eEF1A2 and utrophin A. Our results show that transient overexpression of eEF1A2 in mouse muscles causes an increase in IRES-mediated translation of utrophin A. Through the assessment of our screen, we reveal 7 classes of FDA-approved drugs that increase eEF1A2 and utrophin A protein levels. Treatment of mdx mice with the 2 top leads results in multiple improvements of the dystrophic phenotype. Here, we report that IRES-mediated translation of utrophin A via eEF1A2 is a critical mechanism of regulating utrophin A expression and reveal the potential of repurposed drugs for treating DMD via this pathway. One potential approach for the treatment of Duchenne muscular dysrophy is to increase expression of the dystrophin homolog utrophin. Here, the authors show that eEF1A2 regulates utrophin expression, and show that 2 FDA-approved drugs upregulate eEIF1A2 and utrophin level in mice, leading to improvement of the dystrophic phenotype. |
| Databáze: | OpenAIRE |
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