CE12 - Génétique, génomique et ARN

RNA metabolism and astrocyte dysfunction in myotonic dystrophy – ASTROMYOD

Submission summary

Perturbations of RNA homeostasis are implicated in the aetiology of several human conditions, for which myotonic dystrophy type 1 (DM1) is a paradigmatic example. DM1 is the most common form of inherited neuromuscular disease in adults, but it affects patients of all ages, in multiple tissues and cell types. The neurological manifestations are exceptionally debilitating, however important gaps still exist in our understanding of brain disease. DM1 molecular pathogenesis involves primarily alterations in the activity of MBNL proteins, an important family of RNA-binding proteins that play a plethora of roles in RNA processing, including the regulation of alternative splicing, polyadenylation and intracellular trafficking of transcripts. Such features, notably the RNA distribution into subcellular domains, are critical for the functional plasticity of brain cells, including astrocytes - a highly ramified and compartmentalized cell type. We have recently collected strong evidence of astrocyte abnormalities in DM1, suggesting a non-neuronal component in this disorder. In this project we will investigate how the DM1 mutation disturbs astrocyte function through altered MBNL protein activity and defective RNA processing, and how these defects ultimately lead to brain dysfunction. To this end, we will combine the multidisciplinary expertise of four complementary research partners and their relevant disease models (transgenic mice, iPSC and organoids). Transcriptomics, bioinformatics and high-resolution imaging will elucidate the mechanisms behind DM1 brain disease, as well as fundamental aspects of RNA biology in astrocytes. Importantly, our findings will corroborate the emerging role of astrocytes in neurological disease. Through the identification of the molecular pathways perturbed in DM1, and the development of new mouse and human disease models, we will establish rational grounds and powerful tools to respond to the urgent therapeutic needs for this condition.

Project coordination

Mario Gomes-Pereira (Institut national de la sante et de la recherche medicale)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


CIRB Centre Interdisciplinaire de Recherche en Biologie
CRM Institut national de la sante et de la recherche medicale
I-STEM Institut national de la sante et de la recherche medicale

Help of the ANR 617,296 euros
Beginning and duration of the scientific project: December 2022 - 36 Months

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