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Prion disease-associated retinal degeneration is attributed to PrP-scrapie (PrP Sc ), a misfolded isoform of prion protein (PrP C ) that accumulates in the neuroretina. However, a lack of temporal and spatial correlation between PrP Sc  and cytotoxicity suggests the contribution of host factors. We report retinal iron dyshomeostasis as one such factor. PrP C  is expressed on the basolateral membrane of retinal-pigment-epithelial (RPE) cells, where it mediates uptake of iron by the neuroretina. Accordingly, the neuroretina of PrP-knock-out mice is iron-deficient. In RPE19 cells, silencing of PrP C  decreases ferritin while over-expression upregulates ferritin and divalent-metal-transporter-1 (DMT-1), indicating PrP C -mediated iron uptake through DMT-1. Polarization of RPE19 cells results in upregulation of ferritin by ~10-fold and β-cleavage of PrP C , the latter likely to block further uptake of iron due to cleavage of the ferrireductase domain. A similar β-cleavage of PrP C  is observed in mouse retinal lysates. Scrapie infection causes PrP Sc  accumulation and microglial activation, and surprisingly, upregulation of transferrin despite increased levels of ferritin. Notably, detergent-insoluble ferritin accumulates in RPE cells and correlates temporally with microglial activation, not PrP Sc  accumulation, suggesting that impaired uptake of iron by PrP Sc  combined with inflammation results in retinal iron-dyshomeostasis, a potentially toxic host response contributing to prion disease-associated pathology.

Prion protein facilitates retinal iron uptake and is cleaved at the β-site: Implications for retinal iron homeostasis in prion disorders