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

Author

Listed:
  • Christine Péladeau

    (University of Ottawa
    Centre for Neuromuscular Disease)

  • Nadine Adam

    (University of Ottawa
    Centre for Neuromuscular Disease)

  • Lucas M. Bronicki

    (University of Ottawa
    Centre for Neuromuscular Disease)

  • Adèle Coriati

    (University of Ottawa)

  • Mohamed Thabet

    (University of Ottawa)

  • Hasanen Al-Rewashdy

    (University of Ottawa
    Centre for Neuromuscular Disease)

  • 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
    Centre for Neuromuscular Disease)

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.

Suggested Citation

  • Christine Péladeau & Nadine Adam & Lucas M. Bronicki & Adèle Coriati & Mohamed Thabet & Hasanen Al-Rewashdy & Jason Vanstone & Alan Mears & Jean-Marc Renaud & Martin Holcik & Bernard J. Jasmin, 2020. "Identification of therapeutics that target eEF1A2 and upregulate utrophin A translation in dystrophic muscles," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15971-w
    DOI: 10.1038/s41467-020-15971-w
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