Modulation of proteinase K-resistant prion protein in cells and infectious brain homogenate by redox iron: implications for prion replication and disease pathogenesis.
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.
Basu
Subhabrata
S
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Mohan
Maradumane L
ML
Luo
Xiu
X
Kundu
Bishwajit
B
Kong
Qingzhong
Q
Singh
Neena
N
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*
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