Mario Gomes-Pereira and his team* have just published a paper in Nature Communications** on the toxicity of mutant RNA that alters the morphology, adhesion and migration of astrocytes in mice and humans with myotonic dystrophy type 1 (DM1). Interview with Mario Gomes-Pereira.
What is the background to this work?
DM1 is a neuromuscular disease that also affects the brain, with very diverse neurological manifestations that vary from subtle signs to the very severe symptoms. Brain dysfunction is very marked in the early forms of the disease, and is characterised by intellectual deficiency and behavioural changes. In adults, the neurological impairment is more subtle but also very typical, affecting mainly the capacity of mental planning adaptation and the flexibility of reasoning. Behavioural changes are also observed in adults.
DM1 is due to the abnormal expansion of a CTG trinucleotide repeat in the DMPK gene, leading to the formation of toxic RNA aggregates (or foci) inside the cell nucleus, disrupting the metabolism of other messenger RNAs and several cellular functions.
The brain is composed of several cell types. In addition to neurons, there are glial cells: astrocytes, oligodendrocytes and microglia. Glial cells maintain homeostasis, and play a structural, metabolic and neurochemical support role.
We know that the DMPK gene is highly expressed in astrocytes, so we wondered whether these cells show deleterious accumulation of RNA foci and abnormalities that could contribute to the cognitive and behavioural impairment in DM1.
What was the aim of this study and how did you go about it?
We are trying to understand the molecular and cellular basis of DM1 brain dysfunction. In DM1, there is no obvious overall neurodegeneration. Instead, the disease mainly involves a deterioration of certain brain functions, which overall is very disabling for the daily life of patients. Our hope is to be able to act on deregulated brain functions, in order to improve the quality of life of patients. To this end, we have been using a transgenic mouse model of the disease (the DMSXL line created by Geneviève Gourdon), which expresses the human mutation in several types of brain cells, producing toxic RNAs. Our aim is to determine which cells are most affected, and in particular to study the impact of DM1 on astrocytes.
What results did you obtain?
We have shown that DMSXL astrocytes accumulate more abundant RNA foci, compared to neurons, which disrupt their morphology, both in the mouse brain and in cell culture. Astrocytes carrying the mutation are smaller and less ramified. The neurological impairment seems, therefore, to have a non-neuronal component.
Furthermore, via RNA sequencing, we have shown that toxic RNA repeats have an impact on the expression of genes that control cell morphology, adhesion and the cytoskeleton of astrocytes, probably compromising their role in supporting and regulating synaptic function.
Finally, to study the impact of defective astrocytes on neurons, we used co-culture cell systems. By culturing neurons in the presence of astrocytes with or without the DM1 mutation, we found that astrocytes from the DMSXL mice alter neuritogenesis, indirectly impacting neuronal biology.
What conclusions did you draw from these data?
These results imply that we need to shift away from the neuro-centric view of brain damage in DM1. Some laboratories are currently trying to develop new therapies, notably the REDs team at the MRC. We have not yet identified the most relevant therapeutic targets in astrocytes, as there are potentially several genes involved. However, our data already opens a new and important line of thought regarding new gene therapy tools: in order to better target the cognitive and behavioural impairment of DM1, it will not be enough to target neurons alone, but also astrocytes and most probably other non-neuronal cells.
** Dincã DM, Lallemant L, González-Barriga A, Cresto N, Braz SO, Sicot G, Pillet LE, Polvèche H, Magneron P, Huguet-Lachon A, Benyamine H, Azotla-Vilchis CN, Agonizantes-Juárez LE, Tahraoui-Bories J, Martinat C, Hernández-Hernández O, Auboeuf D, Rouach N, Bourgeois CF, Gourdon G, Gomes-Pereira M. Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes. Nat Commun. 2022 Jul 4;13(1):3841. doi: 10.1038/s41467-022-31594-9. Erratum in: Nat Commun. 2022 Jul 14;13(1):4091. PMID: 35789154; PMCID: PMC9253038.