Ablation of progranulin augments microglial activation and accelerates prion progression

Mutations or polymorphisms in GRN, encoding the CNS glycoprotein progranulin (PGRN), have been linked to several neurodegenerative diseases. In this study, we explored the role of PGRN in prion diseases. We observed that prion infection upregulated microglial PGRN expression. Following intracerebral inoculation with RML6 prions, Grn^-/- mice exhibited accelerated disease progression compared to Grn^+/- and Grn^+/+ littermates. Histological analysis revealed augmented microglial activation in Grn^-/- mice. Temporal analysis revealed enhanced early microglial activation and prion clearance at 120 dpi, followed by excessive complement activation but inadequate clearance by 150 dpi. Additionally, Grn^-/- brains exhibited exacerbated astrogliosis and vacuolation. RNA-seq analysis indicated that complete PGRN deficiency in prion-infected mice shifted microglia from homeostatic to pro-inflammatory states. Notably, microglia-specific depletion of PGRN did not affect prion pathogenesis, suggesting that PGRN deficiency affects microglial activation and prion progression in a non-cell autonomous manner. These findings suggest that microglia respond to prion infection in a stepwise manner, and PGRN plays a critical role in modulating prion-induced microglial activation. Our results highlight the neuroprotective role of PGRN in prion disease and suggest that supplementation or boosting expression of PGRN could represent a promising therapeutic strategy.