Daunorubicin reduces MBNL1 sequestration caused by CUG-repeat expansion and rescues cardiac dysfunctions in a Drosophila model of myotonic dystrophy
| Autor: | Chakraborty M, Sellier C, Ney M, Pascal V, Charlet-Berguerand N, Artero R, Llamusi B |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Disease Models & Mechanisms r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA instname r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF) r-CIPF: Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF) Centro de Investigación Principe Felipe (CIPF) |
| ISSN: | 1754-8403 |
| Popis: | Myotonic dystrophy (DM) is a dominantly inherited neuromuscular disorder caused by expression of mutant myotonin- protein kinase (DMPK) transcripts containing expanded CUG repeats. Pathogenic DMPK 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 Muscleblind (Mbl), the Drosophila MBNL 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 Mbl sequestration in Drosophila DM1 cardiomyocytes, resulting in missplicing 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. |
| Databáze: | OpenAIRE |
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