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Updated: Jul 31, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Peroxisomal defects in microglial cells induce a disease-associated microglial signature
Quentin Raas1, Ali Tawbeh1, Mounia Tahri-Joutey1,2
1Laboratoire Bio-PeroxIL EA7270, University of Bourgogne, Dijon, France.
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.
Insights
Peroxisomal defects in microglial cells trigger a disease-associated microglial (DAM) signature, impacting lipid metabolism and contributing to neurodegeneration in X-linked adrenoleukodystrophy (X-ALD). This study reveals microglial dysfunction as a key factor in peroxisomal disorders.
Area of Science:
- Neurobiology
- Cell Biology
- Genetics
Background:
- Microglial cells maintain brain homeostasis but adopt a disease-associated microglial (DAM) signature in pathological conditions.
- In X-linked adrenoleukodystrophy (X-ALD), microglial defects precede myelin loss and may drive neurodegeneration.
- Peroxisomal β-oxidation defects are central to X-ALD pathogenesis.
Purpose of the Study:
- To investigate the impact of peroxisomal gene mutations on microglial cells.
- To characterize the molecular signature of microglia in a model of X-ALD.
- To determine if peroxisomal defects induce a DAM-like phenotype in microglia.
Main Methods:
- Utilized BV-2 microglial cell lines with peroxisomal gene mutations.
- Performed RNA-sequencing to analyze gene expression changes.
- Confirmed protein level changes for selected genes and assessed DAM protein secretion.
Main Results:
- Identified large-scale gene reprogramming in lipid metabolism, immune response, and cell signaling pathways.
- Observed a DAM-like signature with altered homeostatic and disease-associated genes.
- Confirmed cholesterol accumulation and altered autophagy patterns.
- Demonstrated increased expression and secretion of DAM proteins in mutant microglial cells.
Conclusions:
- Peroxisomal defects in microglia extend beyond lipid metabolism, inducing a pathological phenotype.
- Microglial dysfunction is a significant contributor to the pathogenesis of peroxisomal disorders like X-ALD.
- The study provides a cellular model for investigating microglial roles in X-ALD and related diseases.
