Multi-omic profiling (scRNA-seq + epigenetic) of myeloid cells from aged progranulin-deficient (Grn-/-) mouse brains was used to map how lysosomal dysfunction shapes microglial cell states and identify the transcription factors driving maladaptive responses.
A GPNMB+ microglial subpopulation emerged in Grn-/- mice with hallmarks of lysosomal stress (lipofuscinosis, metabolic and lipid dysregulation); MITF/TFE transcription factor motifs were enriched at active enhancers, and their deletion reversed the Grn-/--specific transcriptional signature. Compensatory GPNMB upregulation promoted lysosomal acidification, while myeloid-specific GPNMB loss worsened neurotoxicity.
Findings are based on a mouse (Grn-/-) model, limiting direct translation to human neurodegeneration. The study does not test therapeutic rescue of lysosomal function in vivo beyond genetic manipulations. Causal ordering between epigenetic changes and lysosomal dysfunction in human disease remains unestablished.
GPNMB and MITF/TFE signaling in microglia are candidate therapeutic targets for progranulin-linked neurodegeneration (e.g., frontotemporal dementia). Lysosomal deacidification broadly recapitulates the maladaptive microglial state, suggesting lysosomal pH restoration as a potential intervention strategy.
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