Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 50, Pages 25203-25213Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1820297116
Keywords
chloroquine; myotonic dystrophy; muscleblind; therapy
Categories
Funding
- Ministerio de Economia y Competitividad from the European Regional Development Fund [SAF2015-64500-R]
- Conselleria d'Educacio, Investigacio, Cultura i Esport (Generalidad Valenciana) [ACIF/2018/071, GRISOLIAP/2018/098]
- European Union through Programa Operativo del Fondo Europeo de Desarrollo Regional of Comunitat Valenciana 2014-2020
- [APOSTD2017/077]
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Myotonic dystrophy type 1 (DM1) is a life-threatening and chronically debilitating neuromuscular disease caused by the expansion of a CTG trinucleotide repeat in the 3' UTR of the DMPK gene. The mutant RNA forms insoluble structures capable of sequestering RNA binding proteins of the Muscleblind-like (MBNL) family, which ultimately leads to phenotypes. In this work, we demonstrate that treatment with the antiautophagic drug chloroquine was sufficient to up-regulate MBNL1 and 2 proteins in Drosophila and mouse (HSALR) models and patient-derived myoblasts. Extra Muscleblind was functional at the molecular level and improved splicing events regulated by MBNLs in all disease models. In vivo, chloroquine restored locomotion, rescued average cross-sectional muscle area, and extended median survival in DM1 flies. In HSALR mice, the drug restored muscular strength and histopathology signs and reduced the grade of myotonia. Taken together, these results offer a means to replenish critically low MBNL levels in DM1.
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