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Transcription profiles of mouse microglia isolated by FACS from WT and Grn KO animals, separated by lipofuscin levels [hex001110]

ABSTRACT: Previous single-cell RNA sequencing of microglia from aged WT and Grn KO mice revealed a microglial subset with transcriptomic signatures that were highly specific to Grn KO. Immunohistochemistry analysis suggested that this population was also characterized by high lipofuscin burden. In this study, we used bulk RNAseq to investigate whether these transcriptomic markers were affected by lipofuscinosis. Microglia were sorted by FACS from dissociated brain tissue of 19-month-old mice of WT or Grn KO background. Cells expressing microglial markers (CD45+/CD11b+) were selected and stratified into lipofuscin ‘low’ or ‘high’ subpopulations, based on autofluorescence. 1,000 cells were collected per sample and were processed and analyzed for bulk RNA sequencing. Results indicated a consistent upregulation of Grn KO-specific genes in microglia from the Grn KO background, which were further enriched ‘high’ vs. ‘low’ lipofuscin cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE327960 | GEO | 2026/07/20

REPOSITORIES: GEO

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Project description:Myeloid cells maintain tissue homeostasis via the recognition, engulfment, and lysosomal clearance of dying cells and cellular debris, which is often accompanied by changes from homeostatic to reactive states. While a role for phagocytic receptors in gating these transitions has been described, less is known about if and how lysosomes can contribute to transcriptional and functional plasticity. To determine how lysosomal health impacts myeloid cell states, we evaluated microglia and macrophages deficient for progranulin (encoded by Grn), a lysosomal protein with pleiotropic functions whose loss is associated with several neurodegenerative diseases. Single-cell RNA-sequencing of the aged mouse brain identified a Grn knockout (KO)-specific microglial subpopulation marked by high GPNMB expression that displays hallmarks of lysosomal dysfunction, including lipofuscin accumulation. Epigenetic analysis of aged microglia revealed MITF/TFE transcription factors as key mediators of the transcriptional states associated with Grn deficiency. In addition to identifying a core myeloid cell transcriptional response to diverse lysosomal stressors, targeted perturbations of various lysosomal properties in vitro uncovered a cell autonomous, TREM2-independent, response to lysosomal deacidification (via v-ATPase or VPS34 loss of function) that overlaps with Grn KO microglia phenotypes, including the induction of a lysosomal gene program, increased proliferation, and secretion of pro-inflammatory cytokines. Compound loss-of-function approaches established GPNMB upregulation upon lysosomal stress is required for the compensatory response to enhance lysosomal function via promoting acidification. Finally, pharmacological endolysosomal reacidification through sodium/proton exchanger inhibition partially rescued Grn KO microglia phenotypes. Overall, these data establish a fundamental link between lysosomal health and myeloid cell epigenetic, transcriptional, and functional states observed in neurodegeneration models.

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Transcription profiles of mouse microglia isolated by FACS from WT and Grn KO animals, separated by lipofuscin levels [hex001110]

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