文章基本信息

标题：Prion protein facilitates retinal iron uptake and is cleaved at the β-site: Implications for retinal iron homeostasis in prion disorders
本地全文：下载
作者：Abhishek Asthana ; Shounak Baksi ; Ajay Ashok 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2017
卷号：7
期号：1
DOI：10.1038/s41598-017-08821-1
语种：English
出版社：Springer Nature
摘要：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.