Résumé :
|
Myotonic Dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is a multisystemic inherited disorder that affects skeletal muscle, heart and brain. DM1 is caused by a CTG expansion mutation located on the 3’untranslated region of the dystrophia myotonica protein kinase (dmpk) gene. The pathogenesis results primarily from a toxic gain of function of RNAs bearing long CUG tracks. Toxic RNAs accumulate in the nucleus and sequester RNA binding proteins. Their subsequent loss of function alters developmentally regulated alternative splicing, thereby causing specific symptoms of the disease. We previously showed in DM1 brain a modified splicing of Tau, consisting on a reduced inclusion of Tau exons 2/3. Tau is a microtubule associated protein expressed in brain and muscle. Tau is also the main component of neurofibrillary degeneration, a pathological lesion observed in DM1 brain and in other neurodegenerative disorders referred to as Taupathies. Interestingly, our analyses on DM1 muscle biopsies also revealed a mis-splicing of Tau primary transcript similar to the one observed in brain. This result suggests a possible common mechanism of alternative splicing in brain and muscle. To address this question, we investigate further the potential role of the splicing factor Muscleblind like 1 (MBNL1) on Tau splicing. MBNL1 is expressed in both tissues and was found sequestered by expanded RNAs. Herein, we show that depletion of MBNL1 expression by small RNA interferences reduces inclusion of Tau exons 2/3, as observed in DM1 brain and muscle tissue. Interestingly, we also show that ectopic expression of MBNL1 alone does not modify Tau splicing whereas co-expressed along with expanded RNAs it restores Tau mis-splicing. Altogether, our results suggest a potential common mechanism responsible of Tau mis-splicing in brain and muscle tissue where the splicing factor MBNL1 would be one of the main actors.
|