Deregulation of alternative splicing by toxic CUG repeats in astrocytes from a mouse model of myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is a severe multisystemic disorder mediated by toxic RNA and abnormal RNA processing. Although splicing defects can explain some key disease symptoms, important gaps exist in our understanding of brain pathology, impeding the rational development of therapies. Here we investigated the different impact of DM1 on astrocytes, using a transgenic mouse model that expresses DM1-associated toxic CUG repeats-containing RNA. RNA sequencing revealed critical missplicing in transcripts that regulate cell adhesion, cytoskeleton and morphogenesis specific to astrocytes. These defects correlated with functional abnormalities in the assembly of focal adhesions and migration in culture, as well as defective astrocyte ramification and reorientation in vivo. Our results demonstrate that DM1 is critically deleterious for the adhesion and morphogenesis of astrocytes, possibly compromising the support and regulation of synaptic function . Overall design: In order to better understand astrocyte contribution to DM1 brain disease, we used the DMSXL mouse model. Transgenic DMSXL mice carry more than 1,000 CTG repeats in the human DMPK locus (Gomes-Pereira et al., 2007). RNA samples were prepared from WT and DMSXL primary astrocytes, grown for 15 days in vitro.