Journal Article

Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes

Sicot, Géraldine, Lallemant, Louison, Braz, Sandra O., Tahraoui-Bories, Julie, Martinat, Cécile, Bourgeois, Cyril F., Rouach, Nathalie, Cresto, Noémie, Gomes-Pereira, Mário, Pillet, Laure-Elise, Hernández-Hernández, Oscar, Auboeuf, Didier, Huguet-Lachon, Aline, Azotla-Vilchis, Cuauhtli N., González-Barriga, Anchel, Agonizantes-Juárez, Luis E., Benyamine, Hélène, Gourdon, Geneviève, Dincã, Diana M., Magneron, Paul, Polvèche, Hélène

2022

Overview

Brain dysfunction in myotonic dystrophy type 1 (DM1), the prototype of toxic RNA disorders, has been mainly attributed to neuronal RNA misprocessing, while little attention has been given to non-neuronal brain cells. Here, using a transgenic mouse model of DM1 that expresses mutant RNA in various brain cell types (neurons, astroglia, and oligodendroglia), we demonstrate that astrocytes exhibit impaired ramification and polarization in vivo and defects in adhesion, spreading, and migration. RNA-dependent toxicity and phenotypes are also found in human transfected glial cells. In line with the cell phenotypes, molecular analyses reveal extensive expression and accumulation of toxic RNA in astrocytes, which result in RNA spliceopathy that is more severe than in neurons. Astrocyte missplicing affects primarily transcripts that regulate cell adhesion, cytoskeleton, and morphogenesis, and it is confirmed in human brain tissue. Our findings demonstrate that DM1 impacts astrocyte cell biology, possibly compromising their support and regulation of synaptic function. Myotonic dystrophy type 1 (DM1) is characterized by debilitating neurological symptoms. Dinca et al. demonstrate the pronounced impact of DM1 on the morphology and RNA metabolism of astrocytes. Their findings suggest astroglial pathology in DM1 brain dysfunction.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/51 / 14 / 14/19 / 38 / 38/32 / 38/91 / 631/378/1689 / 631/378/2596/1308 / 631/80/79/2027 / 64/60 / Adhesion / Animals / Astrocytes / Astrocytes / metabolism / Biochemistry, Molecular Biology / Biocompatibility / Brain / Cell adhesion / Cytoskeleton / Dystrophy / Gene expression / Genomics / Glial cells / Humanities and Social Sciences / Humans / Life Sciences / Mice / Mice, Transgenic / Morphogenesis / Morphology / multidisciplinary / Myotonic dystrophy / Myotonic Dystrophy / metabolism / Neurobiology / Neurons / Neurons and Cognition / Oligodendrocytes / Phenotypes / Ribonucleic acid / RNA / RNA / genetics / RNA-Binding Proteins / metabolism / Science / Science (multidisciplinary) / Signs and symptoms / Tissue Adhesions / Toxicity / Transgenic mice