Presented on September 9th, 2023.

Mário Gomes-Pereira, PhD
Sorbonne Université, Inserm, Association Institut de Myologie, Paris, France

Brain function relies on the complex interplay between highly specialised and ramified neuronal and glia cells, which together regulate cognition, emotion and sleep/wake cycles. All these are profoundly affected in myotonic dystrophy type 1 (DM1). While it is established that mutant RNA accumulates in the nucleus of DM1 cells and perturbs the activity of key RNA-binding proteins, our understanding of how different cell types in the central nervous system drive brain pathology remains incomplete. To bridge this knowledge gap, we sought to investigate the impact of DM1 RNA toxicity on different brain cells, taking advantage of a unique transgenic mouse model that preserves the spatiotemporal expression of an expanded DMPK transgene. We found a marked deleterious effect of toxic RNA on glial cells, characterized by impaired astrocyte ramification and delayed myelination in vivo, as well as defective morphology, adhesion and migration in primary cultures. Glial phenotypes were associated with pronounced spliceopathy of cytoskeleton-related transcripts in both astrocytes and oligodendrocytes, which recreated a molecular signature of impaired differentiation. We suggest that RNA toxicity in glia cells disrupts the intricate neuron-glia crosstalk and impacts neuronal physiology. By focusing our investigation on glial cells, which are often overshadowed by neurons, our research sheds light on the underlying mechanisms of DM1 in the brain. Importantly, our data strengthen the need to target both neuronal and non-neuronal cells in future therapeutic strategies designed to alleviate the neuropsychological symptoms of the disease.

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