Identification of therapeutics that target eEF1A2 and upregulate utrophin A translation in dystrophic muscles

Christine Péladeau, Nadine Adam, Lucas M. Bronicki, Adèle Coriati, Mohamed Thabet, Hasanen Al-Rewashdy, Jason Vanstone, Alan Mears, Jean-Marc Renaud, Martin Holcik and Bernard J. Jasmin ()
Additional contact information
Christine Péladeau: University of Ottawa
Nadine Adam: University of Ottawa
Lucas M. Bronicki: University of Ottawa
Adèle Coriati: University of Ottawa
Mohamed Thabet: University of Ottawa
Hasanen Al-Rewashdy: University of Ottawa
Jason Vanstone: Children’s Hospital of Eastern Ontario Research Institute
Alan Mears: Children’s Hospital of Eastern Ontario Research Institute
Jean-Marc Renaud: University of Ottawa
Martin Holcik: Carleton University
Bernard J. Jasmin: University of Ottawa

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-15971-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15971-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-15971-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().