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Poster De Conférence Année : 2019

Investigating oligodendrocyte dysfunction in DM1 brain disease

Résumé

Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat expansion disorder that affects multiple tissues, notably the CNS. Brain involvement is demonstrated by debilitating neurological symptoms and structural changes, including predominant white matter lesions. DM1 is caused by the abnormal expansion of a CTG repeat in the 3’UTR of the DMPKgene. Expanded DMPK transcripts are toxic to the cell: they accumulate in RNA aggregates (foci), affect RNA-binding proteins and deregulate the RNA processing and metabolism of downstream transcripts. However, we still do not know which cell types and molecular pathways are primarily affected in the brain to explain the etiology of the neurological manifestations. To address this question we are using a transgenic mouse model of DM1. The DMSXL mice express expanded DMPKtranscripts in multiple tissues. In addition to the accumulation of RNA foci in neurons and astrocytes, we have found toxic RNA accumulation in oligodendrocytes (OLs) in vivo, as well as missplicing in OLs isolated from adult DMSXL brains. To investigate the functional consequences of RNA toxicity in OL physiology, we investigated primary OL cultures by videomicroscopy. Despite normal proliferation in culture, DMSXL OLs precursors exhibit signs of defective migration and impaired differentiation into ramified OLs. Interestingly OLs show pronounced splicing defects that recreate the profiles of precursor cells. We then investigated if the differentiation defects in cultured OLs were found in vivo. Young DMSXL mice show lower expression of myelin protein markers (myelin basic protein, MBP), as well as a decreased number of mature OLs, reduced thickness and lower density of myelinated axons in the corpus callosum. Together these results suggest a myelination delay in response to the DM1 repeat mutation. To decipher the mechanisms behind OL and myelin phenotypes, we have combined proteomics and RNA sequencing approaches, to find events and pathways specifically deregulated in this cell type. Interestingly, myelin misregulation may be accounted for, at least partially, by a significant increase in the protein levels of myelin expression factor 2 (MYEF2), a repressor of MBP. Furthermore, gene ontology analysis suggests the abnormal expression of structural and regulatory components of the cytoskeleton, as well as critical signaling pathways involved in cell motility and differentiation. Revealing the mechanisms of OL impairment in DM1 will help us better understand brain disease symptoms and identify new therapeutic targets.
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Dates et versions

hal-04010005 , version 1 (01-03-2023)

Identifiants

  • HAL Id : hal-04010005 , version 1

Citer

Sandra Braz, Raphael Blain, Cyril F Bourgeois, Aline Huguet-Lachon, Alain Schmitt, et al.. Investigating oligodendrocyte dysfunction in DM1 brain disease. The European Meeting on Glial Cells in Health and Disease, Jul 2019, Porto, Portugal. ⟨hal-04010005⟩
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