NR ATXY
AU Orem,N.R.; Geoghegan,J.C.; Deleault,N.R.; Kascsak,R.; Supattapone,S.
TI Copper (II) ions potently inhibit purified PrPres amplification
QU Journal of Neurochemistry 2006 Mar; 96(5): 1409-15
PT journal article
AB The structural conversion of a host protein, PrPc, into a protease-resistant isoform, PrPres, is the central event in the pathogenesis of infectious prion diseases. Purification of native PrPc molecules from hamster brain by either cation exchange or immobilized chelator chromatographic resins yielded preparations that supported efficient amplification of scrapie-induced PrPres in vitro. Using these purified preparations, we determined that in vitro PrPres amplification was inhibited by CuCl2 and ZnCl2 at IC50 concentrations of approximately 400 nm and 10 microM, respectively. In contrast, 100 microM MnCl2 did not directly inhibit PrPres amplification or block Cu2+-mediated inhibition. Additionally, the inhibition of PrPres amplification by Cu2+ ions could be reversed by addition of either neocuproine or imidazole. Cu2+ inhibited PrPres amplification in both the presence and absence of stimulatory polyanion molecules. These biochemical findings support the hypothesis that Cu2+ ions might regulate the pathogenesis of prion diseases in vivo.
MH Animals; Brain/metabolism; Brain Chemistry/*drug effects; Cation Exchange Resins; Cell-Free System; Comparative Study; Copper/*pharmacology; Cricetinae; Dose-Response Relationship, Drug; Edetic Acid/pharmacology; Enzyme Inhibitors/pharmacology; Imidazoles/pharmacology; In Vitro; Inhibitory Concentration 50; PrPc Proteins/chemistry/*metabolism; PrPsc Proteins/chemistry/metabolism; Protein Binding/drug effects; Protein Conformation; Protein Folding; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
AD Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire, USA
SP englisch
PO England