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

Sci Rep. 2017 Aug 29;7(1):9600. doi: 10.1038/s41598-017-08821-1.

Abstract

Prion disease-associated retinal degeneration is attributed to PrP-scrapie (PrPSc), a misfolded isoform of prion protein (PrPC) that accumulates in the neuroretina. However, a lack of temporal and spatial correlation between PrPSc and cytotoxicity suggests the contribution of host factors. We report retinal iron dyshomeostasis as one such factor. PrPC 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 PrPC decreases ferritin while over-expression upregulates ferritin and divalent-metal-transporter-1 (DMT-1), indicating PrPC-mediated iron uptake through DMT-1. Polarization of RPE19 cells results in upregulation of ferritin by ~10-fold and β-cleavage of PrPC, the latter likely to block further uptake of iron due to cleavage of the ferrireductase domain. A similar β-cleavage of PrPC is observed in mouse retinal lysates. Scrapie infection causes PrPSc 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 PrPSc accumulation, suggesting that impaired uptake of iron by PrPSc combined with inflammation results in retinal iron-dyshomeostasis, a potentially toxic host response contributing to prion disease-associated pathology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biological Transport
  • Cricetinae
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Homeostasis
  • Humans
  • Iron / metabolism*
  • Mice
  • Mice, Knockout
  • PrPC Proteins / genetics
  • PrPC Proteins / metabolism
  • PrPSc Proteins / genetics
  • PrPSc Proteins / metabolism
  • Prion Diseases / etiology
  • Prion Diseases / metabolism
  • Prion Proteins / chemistry
  • Prion Proteins / genetics
  • Prion Proteins / metabolism*
  • Proteolysis
  • Retina / metabolism*

Substances

  • PrPC Proteins
  • PrPSc Proteins
  • Prion Proteins
  • Iron