Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes
Résumé
Introduction: Brain dysfunction in neurological diseases is frequently mediated by the impairment of neuronal and non-neuronal cells. Although DMPK gene expression is higher in cortical astrocytes than in neurons isolated from adult human and mouse brains, the contribution of astroglia to DM1 brain disease has been poorly investigated.
Methods: Transgenic DMSXL mice express expanded human DMPK transcripts in multiple cell types of the brain, providing a good model to investigate the impact of RNA toxicity on astroglia.
Results: DMSXL astrocytes exhibit impaired ramification and polarization in vivo, as well as defects in adhesion, spreading and migration in culture. In line with these pronounced phenotypes, DMSXL astrocytes express high levels of toxic RNA and accumulate abundant RNA foci, relative to neurons. RNA sequencing revealed MBNL-dependent RNA spliceopathy, which affects primarily transcripts that regulate cell adhesion, cytoskeleton and morphogenesis. To study the impact of defective astrocytes on neurons, we used co-culture cell systems, and found that DMSXL astrocytes impair neuritogenesis.
Conclusions: We demonstrate that DM1 impacts astrocyte cell biology, possibly compromising the support and regulation of synaptic function through defective neuroglia interplay.