Résumé :
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Myotonic Dystrophy (DM1) is caused by an expansion of CTG repeats in the 3' untranslated region (3'UTR) of DMPK mRNA. The expanded mRNA aggregates in the nucleus and becomes toxic to cells by sequestering and/or misregulating RNA-binding proteins such as MBNL1 and CUGBP1. Here, we show for the first time that the RNA-binding protein Staufen1 is markedly increased in skeletal muscle from DM1 mouse models and patients. In addition, we uncover a new role for Staufen1 in regulating pre-mRNA splicing. More specifically, we demonstrate that Staufen1 can counteract the effects of toxic RNA repeats on alternative splicing of at least two key pre-mRNAs known to be aberrantly spliced in DM1. Finally, we also show the direct involvement of Staufen1 in promoting the nucleo-cytoplasmic transport of expanded DMPK mRNAs. Altogether, our results unravel a novel mechanism involved in DM1 and indicate that Staufen1 can positively modulate the complex DM1 phenotype. It is hoped that this study will lead to a deeper understanding of the DM1 pathology, and in turn uncover new therapeutic targets. This work is supported by the Canadian Institutes of Health Research (CIHR), the Rachel Fund (CIHR - IMHA and Muscular Dystrophy Canada), the Association Franse contre les Myopathies (AFM) and the Muscular Dystrophy Association (USA).
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