Daunorubicin reduces MBNL1 sequestration caused by CUG-repeat expansion and rescues cardiac dysfunctions in a Drosophila model of myotonic dystrophy

• Published in: Disease models & mechanisms 2018-04, Vol.11 (4)
• Main Authors: Chakraborty, Mouli, Sellier, Chantal, Ney, Michel, Pascal, Villa, Charlet-Berguerand, Nicolas, Artero, Ruben, Llamusi, Beatriz
• Format: Article
• Language: English
• Subjects: Alternative Splicing - genetics; Animals; Cardiac arrhythmia; Daunorubicin; Daunorubicin - pharmacology; Disease Models, Animal; Drosophila; Drosophila melanogaster - drug effects; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Heart - drug effects; Heart - physiopathology; Insects; Muscleblind; Musculoskeletal system; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myotonic dystrophy; Myotonic Dystrophy - genetics; Myotonic Dystrophy - physiopathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein Binding - drug effects; Proteins; Reproducibility of Results; RNA Stability - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Survival Analysis; Trinucleotide repeat disorder; Trinucleotide Repeat Expansion - genetics
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.032557

Myotonic dystrophy (DM) is a dominantly inherited neuromuscular disorder caused by expression of mutant myotonin-protein kinase ( ) transcripts containing expanded CUG repeats. Pathogenic RNA sequesters the muscleblind-like (MBNL) proteins, causing alterations in metabolism of various RNAs. Cardiac dysfunction represents the second most common cause of death in DM type 1 (DM1) patients. However, the contribution of MBNL sequestration in DM1 cardiac dysfunction is unclear. We overexpressed ( ), the orthologue, in cardiomyocytes of DM1 model flies and observed a rescue of heart dysfunctions, which are characteristic of these model flies and resemble cardiac defects observed in patients. We also identified a drug - daunorubicin hydrochloride - that directly binds to CUG repeats and alleviates sequestration in DM1 cardiomyocytes, resulting in mis-splicing rescue and cardiac function recovery. These results demonstrate the relevance of Mbl sequestration caused by expanded-CUG-repeat RNA in cardiac dysfunctions in DM1, and highlight the potential of strategies aimed at inhibiting this protein-RNA interaction to recover normal cardiac function.