title: Modulation of proteinase K-resistant prion protein in cells and infectious brain homogenate by redox iron: implications for prion replication and disease pathogenesis.
abstract: The principal infectious and pathogenic agent in all prion disorders is a beta-sheet-rich isoform of the cellular prion protein (PrP(C)) termed PrP-scrapie (PrP(Sc)). Once initiated, PrP(Sc) is self-replicating and toxic to neuronal cells, but the underlying mechanisms remain unclear. In this report, we demonstrate that PrP(C) binds iron and transforms to a PrP(Sc)-like form (*PrP(Sc)) when human neuroblastoma cells are exposed to an inorganic source of redox iron. The *PrP(Sc) thus generated is itself redox active, and it induces the transformation of additional PrP(C), simulating *PrP(Sc) propagation in the absence of brain-derived PrP(Sc). Moreover, limited depletion of iron from prion disease-affected human and mouse brain homogenates and scrapie-infected mouse neuroblastoma cells results in 4- to 10-fold reduction in proteinase K (PK)-resistant PrP(Sc), implicating redox iron in the generation, propagation, and stability of PK-resistant PrP(Sc). Furthermore, we demonstrate increased redox-active ferrous iron levels in prion disease-affected brains, suggesting that accumulation of PrP(Sc) is modulated by the combined effect of imbalance in brain iron homeostasis and the redox-active nature of PrP(Sc). These data provide information on the mechanism of replication and toxicity by PrP(Sc), and they evoke predictable and therapeutically amenable ways of modulating PrP(Sc) load.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Basu
authors.forename: Maradumane L
authors.initials: ML
authors.lastname: Mohan
authors.forename: Xiu
authors.initials: X
authors.lastname: Luo
authors.forename: Bishwajit
authors.initials: B
authors.lastname: Kundu
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Kong
authors.forename: Neena
authors.initials: N
authors.lastname: Singh
mesh_terms: D000368:Aged; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D002712:Chlorides; D003676:Deferoxamine / Q000494:pharmacology; D019286:Endopeptidase K / Q000378:metabolism*; D005290:Ferric Compounds / Q000494:pharmacology; D005293:Ferritins / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000494:pharmacology*; D000090463:Iron Deficiencies; D051379:Mice; D008875:Middle Aged; D010084:Oxidation-Reduction / Q000187:drug effects; D018621:PrPC Proteins / Q000378:metabolism* / Q000472:pathogenicity*; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism*; D011487:Protein Conformation / Q000187:drug effects; D014020:Tissue Extracts / Q000378:metabolism*
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D018621:PrPC Proteins; D018620:PrPSc Proteins; D014020:Tissue Extracts; D005293:Ferritins; D007501:Iron; D019286:Endopeptidase K; D003676:Deferoxamine; C024555:ferric chloride