Cytoskeleton abnormalities triggered by toxic CUG RNA repeats in DM1 astrocytes. - Archive ouverte HAL Access content directly
Poster Communications Year : 2023

Cytoskeleton abnormalities triggered by toxic CUG RNA repeats in DM1 astrocytes.

Abstract

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by the abnormal expansion of a non-coding trinucleotide DNA repeats in the 3’UTR of the DMPK gene. Although the muscular symptoms of DM1 are well studied, the dysfunction of the central nervous system (CNS) is also prevalent and can contribute significantly to neurological impairment, characterised by cognitive and memory deficits, as well as emotional disturbance. DM1 pathogenesis is primarily driven by the accumulation of toxic RNA, with mutant DMPK transcripts that contain expanded CUG repeats aggregating in the cell nucleus and forming RNA foci. RNA foci are deleterious because they interfere with key RNA-binding proteins that regulate RNA processing, including alternative splicing. Despite our increasing understanding of muscle disease pathogenesis, the molecular mechanisms underlying brain disease are not fully understood. In particular we do not know the cell types and molecular pathways primarily dysregulated in the brain. We have previously generated a transgenic mouse model of DM1, carrying a large CTG repeat expansion. The DMSXL mice display relevant behaviour phenotypes, impaired synaptic plasticity and increased neuronal firing in specific brain regions. Given the pronounced accumulation of toxic RNA foci in astrocytes, it is our hypothesis that astrocytes are affected by DM1 and contribute to brain pathology through unresolved mechanisms. This view is corroborated by the astrocyte hypotrophy and misorientation that we detected in DMSXL mouse brains. Using global RNA sequencing and phophoproteomics, we found multiple abnormalities in actin cytoskeleton-related transcripts and proteins. Interestingly, DMSXL astrocytes express RNA isoforms typical of immature astroglia, suggesting impaired astrocyte maturation. To assess the impact of such molecular abnormalities on cytoskeleton biology, we are investigating the structure and dynamics of actin microfilaments in DMSXL astrocytes, using high resolution microscopy and biochemical assays. We collected evidence of microfilament misorganisation and destabilisation, demonstrated by a lower ratio of filamentous actin (F-actin) to globular actin (G-actin) in primary DMSXL astrocytes. The molecular evidence of astrocyte cytoskeleton defects along with the morphological abnormalities of astrocytes in vivo and in culture indicate the critical impact of toxic CUG RNA foci on astrocytes biology, which may ultimately affect the support provided to neighbouring neurons at the tripartite synapse and contribute to altered neurotransmission. We will use live cell imaging techniques to further investigate astrocyte cytoskeleton phenotypes in DM1, and to decipher the underlying mechanisms and functional consequences. Our work suggests that DM1 brain disease is not solely mediated by neuronal defects, involving an important glial component. Our findings will reveal new disease intermediates that may offer windows for therapeutic intervention.
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Dates and versions

hal-04005531 , version 1 (26-02-2023)

Identifiers

  • HAL Id : hal-04005531 , version 1

Cite

Paul Magneron, Louison Lallemant, Luis Guillermo Correa Parra, Geneviève Gourdon, Mário Gomes-Pereira. Cytoskeleton abnormalities triggered by toxic CUG RNA repeats in DM1 astrocytes.. French Glial Cell Club, May 2023, Lyon, France. ⟨hal-04005531⟩
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