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

Caredio, D.; Mariutti, G.; Cerisoli, M.; Polzer, L.; Laimeche, Y.; Miracca, G.; Emmenegger, M.; Schmitz, M.; Zerr, I.; De Cecco, E.; Aguzzi, A.

doi:10.1101/2025.02.11.637592

bioRxiv · 10.1101/2025.02.11.637592

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

Caredio, D.·Mariutti, G.·Cerisoli, M.·Polzer, L.·Laimeche, Y.·Miracca, G.·Emmenegger, M.·Schmitz, M.·Zerr, I.·De Cecco, E.·Aguzzi, A.

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Abstract

Neurodegenerative conditions can induce the region-specific emergence of cell states relevant to their pathogenesis. To identify such phenomena, we generated a spatiotemporal transcriptomic atlas of mice infected with the RML prion strain. Thalamus and cerebellum experienced severe neuronal loss, developed intense microgliosis and, starting from 30 weeks post-inoculation, accumulated a novel microglial subpopulation characterized by strong expression of Glycoprotein non-metastatic melanoma protein B (Gpnmb). Elevated GPNMB levels were detected in the cerebrospinal fluid of sCJD patients, suggesting its possible usefulness as a biomarker of disease progression. The transcriptional profile of Gpnmb+ microglia reflected a state of enhanced phagocytic activity with upregulation of genes associated with lysosomal function, including vacuolar ATPase V0 domain subunit d2 (Atp6v0d2) and Galectin-3 (Lgals3). In microglia-like murine BV2 cells, Gpnmb upregulation was induced by soluble find-me signals released during apoptosis, but not by apoptotic bodies or prion accumulation. Likewise, human iPSC-derived microglia showed marked upregulation of GPNMB when co-cultured with apoptotic human neurons. Gpnmb ablation impaired the ability of BV2 cells to clear apoptotic cells, underscoring its role in maintaining microglial phagocytosis. Our findings define Gpnmb microglia as a distinct, apoptosis-driven phagocytic state, linking neuronal loss to microglial activation and positioning it as a key regulator of microglial responses to prion propagation.

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Caredio, D., Mariutti, G., Cerisoli, M., Polzer, L., Laimeche, Y., Miracca, G., Emmenegger, M., Schmitz, M., Zerr, I., De Cecco, E., Aguzzi, A.. 2025-02-12. Gpnmb Defines a Phagocytic State of Microglia Linked to Neuronal Loss in Prion Disease. https://doi.org/10.1101/2025.02.11.637592

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