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

Fiche publication

Date publication

avril 2023

Journal

Frontiers in molecular neuroscience

Auteurs

Membres identifiés du Cancéropôle Est :
Mme TRUNTZER Caroline

Tous les auteurs :
Raas Q, Tawbeh A, Tahri-Joutey M, Gondcaille C, Keime C, Kaiser R, Trompier D, Nasser B, Leoni V, Bellanger E, Boussand M, Hamon Y, Benani A, Di Cara F, Truntzer C, Cherkaoui-Malki M, Andreoletti P, Savary S

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/37138705

Résumé

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.