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

Diana M. Dincã, Louison Lallemant, Anchel González-Barriga, Noémie Cresto, Sandra O. Braz, Géraldine Sicot, Laure-Elise Pillet, Hélène Polvèche, Paul Magneron, Aline Huguet-Lachon, Hélène Benyamine, Cuauhtli N. Azotla-Vilchis, Luis E. Agonizantes-Juárez, Julie Tahraoui-Bories, Cécile Martinat, Oscar Hernández-Hernández, Didier Auboeuf, Nathalie Rouach, Cyril F. Bourgeois, Geneviève Gourdon () and Mário Gomes-Pereira ()
Additional contact information
Diana M. Dincã: Centre de Recherche en Myologie
Louison Lallemant: Centre de Recherche en Myologie
Anchel González-Barriga: Centre de Recherche en Myologie
Noémie Cresto: CNRS, Inserm, Labex Memolife
Sandra O. Braz: Centre de Recherche en Myologie
Géraldine Sicot: Centre de Recherche en Myologie
Laure-Elise Pillet: CNRS, Inserm, Labex Memolife
Hélène Polvèche: Inserm/UEVE UMR861, Université Paris Saclay I-STEM
Paul Magneron: Centre de Recherche en Myologie
Aline Huguet-Lachon: Centre de Recherche en Myologie
Hélène Benyamine: Centre de Recherche en Myologie
Cuauhtli N. Azotla-Vilchis: National Rehabilitation Institute (INR-LGII)
Luis E. Agonizantes-Juárez: National Rehabilitation Institute (INR-LGII)
Julie Tahraoui-Bories: Inserm/UEVE UMR861, Université Paris Saclay I-STEM
Cécile Martinat: Inserm/UEVE UMR861, Université Paris Saclay I-STEM
Oscar Hernández-Hernández: National Rehabilitation Institute (INR-LGII)
Didier Auboeuf: Laboratoire de Biologie et Modelisation de la Cellule, Ecole Normale Superieure de Lyon, CNRS, UMR 5239, Inserm, U1293
Nathalie Rouach: CNRS, Inserm, Labex Memolife
Cyril F. Bourgeois: Laboratoire de Biologie et Modelisation de la Cellule, Ecole Normale Superieure de Lyon, CNRS, UMR 5239, Inserm, U1293
Geneviève Gourdon: Centre de Recherche en Myologie
Mário Gomes-Pereira: Centre de Recherche en Myologie

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31594-9

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