The effects of prion protein expression on metal metabolism.
The prion protein is a glycoprotein that binds metals such as copper and manganese. When converted to a proteinase resistant isoform it is associated with prion diseases such as Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Although, the co-ordination and metal affinity of the prion protein has been well studied, the association of the protein with cellular metal metabolism has been less well investigated. We used transgenic manipulation of prion protein expression and other recombinant techniques to alter expression of known copper binding proteins to investigate the role of the prion protein in copper metabolism. We found that changing the expression of the prion protein alters proteins associated with copper uptake, storage and export from the cell. In addition, alteration in the expression of superoxide dismutases increased prion protein expression dramatically. Reducing copper in the diet decreased expression of the prion protein in the brain while increased dietary manganese dramatically increased the protein's expression. Cellular prion infection also increased the expression of metal transporting proteins and increased cellular manganese concentrations. Overall our results show a close link between cellular resistance to oxidative stress and also copper metabolism. These findings are in line with previous data suggesting that the prion protein is an antioxidant and associated with copper uptake into cells. The disturbance to copper metabolism, as a result of altered prion protein expression clearly demonstrates the important role of the prion protein in copper metabolism. The implication is that prion protein expression has a homeostatic role in copper metabolism.
Kralovicova
Silvia
S
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA27AY, UK.
Fontaine
Sarah N
SN
Alderton
Alexandra
A
Alderman
Julia
J
Ragnarsdottir
K Vala
KV
Collins
Steven J
SJ
Brown
David R
DR
D000818:Animals; D001921:Brain / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D003300:Copper / Q000378:metabolism*; D000079922:Copper Transport Proteins; D000079923:Copper Transporter 1; D004032:Diet; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008345:Manganese / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D018384:Oxidative Stress; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D019076:Transgenes; D000099173:Natural Resistance-associated Macrophage Protein 1; D000099236:Solute Carrier Family 11, Member 2
D027682:Cation Transport Proteins; D003300:Copper; D000079922:Copper Transport Proteins; D000079923:Copper Transporter 1; D007527:Isoenzymes; D008345:Manganese; D018832:Molecular Chaperones; D011328:Prions; D013482:Superoxide Dismutase; D000099173:Natural Resistance-associated Macrophage Protein 1; D000099236:Solute Carrier Family 11, Member 2; C499247:Atox1 protein, mouse; C491962:Ccs protein, mouse; C490077:Slc31a1 protein, mouse