Peroxisomal defects in microglial cells induce a disease-associated microglial signature - INRAE - Institut national de recherche pour l’agriculture, l’alimentation et l’environnement Access content directly
Journal Articles Frontiers in Molecular Neuroscience Year : 2023

Peroxisomal defects in microglial cells induce a disease-associated microglial signature

Maud Boussand
  • Function : Author
Yannick Hamon
  • Function : Author

Abstract

Microglial cells ensure essential roles in brain homeostasis. In pathological condition, microglia adopt a common signature, called disease-associated microglial (DAM) signature, characterized by the loss of homeostatic genes and the induction of disease-associated genes. In X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disease, microglial defect has been shown to precede myelin degradation and may actively contribute to the neurodegenerative process. We previously established BV-2 microglial cell models bearing mutations in peroxisomal genes that recapitulate some of the hallmarks of the peroxisomal β-oxidation defects such as very long-chain fatty acid (VLCFA) accumulation. In these cell lines, we used RNA-sequencing and identified large-scale reprogramming for genes involved in lipid metabolism, immune response, cell signaling, lysosome and autophagy, as well as a DAM-like signature. We highlighted cholesterol accumulation in plasma membranes and observed autophagy patterns in the cell mutants. We confirmed the upregulation or downregulation at the protein level for a few selected genes that mostly corroborated our observations and clearly demonstrated increased expression and secretion of DAM proteins in the BV-2 mutant cells. In conclusion, the peroxisomal defects in microglial cells not only impact on VLCFA metabolism but also force microglial cells to adopt a pathological phenotype likely representing a key contributor to the pathogenesis of peroxisomal disorders.
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hal-04092819 , version 1 (09-05-2023)

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Quentin Raas, Ali Tawbeh, Mounia Tahri-Joutey, Catherine Gondcaille, Céline Keime, et al.. Peroxisomal defects in microglial cells induce a disease-associated microglial signature. Frontiers in Molecular Neuroscience, 2023, 16 (Sec. Brain Disease Mechanisms), pp.1170313. ⟨10.3389/fnmol.2023.1170313⟩. ⟨hal-04092819⟩
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