Gpnmb Defines a Phagocytic State of Microglia Linked to Neuronal Loss in Prion Disease

The reaction of different cell types to prion infections is highly heterogeneous. While neurons experience spine retraction and eventually death, astrocytes and microglia undergo strong activation and proliferation. Here we analyzed the cell-type specific responses to prion diseases by establishing a spatiotemporal transcriptomic atlas of mice infected with RML prion strain. Brain areas with severe neuronal loss, such as the thalamus and cerebellum, experienced intense microgliosis. Starting from 30 weeks post-inoculation, we observed the accumulation of a novel microglial subpopulation characterized by strong expression of Gpnmb in these brain regions. The molecular profile of Gpnmb ⁺ microglia reflected a state of enhanced phagocytic activity with upregulation of genes associated with lysosomal function and degradation, including vacuolar ATPase V0 domain subunit d2 ( Atp6v0d2 ) and Galectin-3 ( Lgals3 ). In microglial-like, murine BV2 cells, Gpnmb upregulation was induced by soluble find-me signals released during apoptosis, but not by apoptotic bodies or prion accumulation. Gpnmb ablation in BV2 cells impaired their ability to phagocytose apoptotic cells, underscoring its essential role in maintaining microglial phagocytosis. Our findings define Gpnmb ⁺ microglia as a distinct, apoptosis-driven phagocytic state, linking neuronal loss to microglial activation in prion disease. The upregulation of GPNMB in sCJD patients, along with its role in apoptotic clearance and lysosomal function, positions it as both a key regulator of microglial responses and a potential biomarker of disease progression.