Progranulin deficiency-induced lysosomal dysfunction drives maladaptive myeloid cell states through the MITF/TFE transcription factors.

Progranulin deficiency causes lysosomal dysfunction that triggers maladaptive myeloid cell states via MITF/TFE transcription factors, impacting neurodegeneration.

• Why it matters: Lysosomal dysfunction in myeloid cells is increasingly linked to neurodegenerative diseases, but the mechanisms connecting lysosomal health and cell states remain unclear.
• What they did: Multi-omic profiling of microglia from aged progranulin-deficient mice revealed a GPNMB-expressing subpopulation with lysosomal stress markers, and epigenetic analysis showed MITF/TFE motifs' involvement; deleting these factors reversed disease-associated signatures.
• The result: Lysosomal perturbations induce a common maladaptive transcriptional program, with GPNMB acting to restore lysosomal function; loss of GPNMB worsens neurotoxicity, highlighting potential therapeutic targets.