NR AYGP
AU Basu,S.; Mohan,M.L.; Luo,X.; Kundu,B.; Kong,Q.; Singh,N.
TI Modulation of proteinase K-resistant prion protein in cells and infectious brain homogenate by redox iron: implications for prion replication and disease pathogenesis.
QU Molecular Biology of the Cell 2007 Sep; 18(9): 3302-12
IA http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1951779
PT journal article; research support, n.i.h., extramural
AB The principal infectious and pathogenic agent in all prion disorders is a beta-sheet-rich isoform of the cellular prion protein (PrPc) termed PrP-scrapie (PrPsc). Once initiated, PrPsc is self-replicating and toxic to neuronal cells, but the underlying mechanisms remain unclear. In this report, we demonstrate that PrPc binds iron and transforms to a PrPsc-like form (*PrPsc) when human neuroblastoma cells are exposed to an inorganic source of redox iron. The *PrPsc thus generated is itself redox active, and it induces the transformation of additional PrPc, simulating *PrPsc propagation in the absence of brain-derived PrPsc. 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 PrPsc, implicating redox iron in the generation, propagation, and stability of PK-resistant PrPsc. Furthermore, we demonstrate increased redox-active ferrous iron levels in prion disease-affected brains, suggesting that accumulation of PrPsc is modulated by the combined effect of imbalance in brain iron homeostasis and the redox-active nature of PrPsc. These data provide information on the mechanism of replication and toxicity by PrPsc, and they evoke predictable and therapeutically amenable ways of modulating PrPsc load.
MH Aged; Animals; Brain/drug effects/*pathology; Cell Line, Tumor; Cell Membrane Permeability/drug effects; Deferoxamine/pharmacology; Endopeptidase K/*metabolism; Ferric Compounds/pharmacology; Ferritins/metabolism; Humans; Iron/deficiency/*pharmacology; Mice; Middle Aged; Oxidation-Reduction/drug effects; PrPc Proteins/*metabolism/*pathogenicity; PrPsc Proteins/metabolism; Prion Diseases/*metabolism; Protein Conformation/drug effects; Tissue Extracts/*metabolism
AD Subhabrata Basu, Maradumane L. Mohan, Xiu Luo, Qingzhong Kong, Neena Singh, Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA; Bishwajit Kundu, Department of Biochemical Engineering and Biotechnology, The Indian Institute of Technology, New Delhi, India 110016
SP englisch
PO USA