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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Cerro-Herreros E,Sabater-Arcis M,Fernandez-Costa JM,Moreno N,Perez-Alonso M,Llamusi B,Artero R

doi

10.1038/s41467-018-04892-4

subject

Has Abstract

pub_date

2018-06-26 00:00:00

pages

2482

issue

1

issn

2041-1723

pii

10.1038/s41467-018-04892-4

journal_volume

9

pub_type

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