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miR-23b and miR-218 silencing increase Muscleblind-like expression and alleviate myotonic dystrophy phenotypes in mammalian models

Author

Listed:
  • Estefania Cerro-Herreros

    (University of Valencia
    Incliva Health Research Institute
    Joint Unit Incliva-CIPF)

  • Maria Sabater-Arcis

    (University of Valencia
    Incliva Health Research Institute
    Joint Unit Incliva-CIPF)

  • Juan M. Fernandez-Costa

    (University of Valencia
    Incliva Health Research Institute
    Joint Unit Incliva-CIPF)

  • Nerea Moreno

    (University of Valencia
    Incliva Health Research Institute
    Joint Unit Incliva-CIPF)

  • Manuel Perez-Alonso

    (University of Valencia
    Incliva Health Research Institute
    Joint Unit Incliva-CIPF)

  • Beatriz Llamusi

    (University of Valencia
    Incliva Health Research Institute
    Joint Unit Incliva-CIPF)

  • Ruben Artero

    (University of Valencia
    Incliva Health Research Institute
    Joint Unit Incliva-CIPF)

Abstract

Functional depletion of the alternative splicing factors Muscleblind-like (MBNL 1 and 2) is at the basis of the neuromuscular disease myotonic dystrophy type 1 (DM1). We previously showed the efficacy of miRNA downregulation in Drosophila DM1 model. Here, we screen for miRNAs that regulate MBNL1 and MBNL2 in HeLa cells. We thus identify miR-23b and miR-218, and confirm that they downregulate MBNL proteins in this cell line. Antagonists of miR-23b and miR-218 miRNAs enhance MBNL protein levels and rescue pathogenic missplicing events in DM1 myoblasts. Systemic delivery of these “antagomiRs” similarly boost MBNL expression and improve DM1-like phenotypes, including splicing alterations, histopathology, and myotonia in the HSALR DM1 model mice. These mammalian data provide evidence for therapeutic blocking of the miRNAs that control Muscleblind-like protein expression in myotonic dystrophy.

Suggested Citation

  • Estefania Cerro-Herreros & Maria Sabater-Arcis & Juan M. Fernandez-Costa & Nerea Moreno & Manuel Perez-Alonso & Beatriz Llamusi & Ruben Artero, 2018. "miR-23b and miR-218 silencing increase Muscleblind-like expression and alleviate myotonic dystrophy phenotypes in mammalian models," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04892-4
    DOI: 10.1038/s41467-018-04892-4
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    Cited by:

    1. Diana M. Dincã & Louison Lallemant & Anchel González-Barriga & Noémie Cresto & Sandra O. Braz & Géraldine Sicot & Laure-Elise Pillet & Hélène Polvèche & Paul Magneron & Aline Huguet-Lachon & Hélène Be, 2022. "Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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