PR002964 (Project)

Description:Myeloid cells respond to tissue damage by clearing dying cells and cellular debris in lysosomes, although how these organelles contribute to transcriptional and functional plasticity is unclear. Here, we evaluated microglia and macrophages lacking progranulin (encoded by Grn), a lysosomal protein linked to neurodegeneration. Single-cell RNA-sequencing of aged mouse brains identified a Grn KO-specific dysfunctional microglial subpopulation marked by high GPNMB expression and lipofuscinosis. Multiomic analysis of this population revealed evidence of metabolic and lysosomal lipid dysregulation. Epigenetic analysis revealed MITF/TFE transcription factors as key mediators of aged Grn KO microglia transcriptional states. Lysosome perturbations with various stressors in cultured myeloid cells uncovered a conserved core transcriptional response, including a response to lysosomal deacidification overlapping with Grn KO microglia phenotypes. Compensatory GPNMB upregulation in Grn KO myeloid cells enhanced lysosomal function by promoting acidification and loss of GPNMB exacerbated non-cell autonomous neurotoxicity. Finally, pharmacological endolysosomal reacidification partially rescued Grn KO microglia phenotypes. Our data establish a fundamental link between lysosomal health and myeloid cell epigenetic, transcriptional, and functional states associated with neurodegeneration.