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

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.