Expression of prion protein increases cellular copper binding and antioxidant enzyme activities but not copper delivery.
The N-terminal region of the prion protein PrP(C) contains a series of octapeptide repeats. This region has been implicated in the binding of divalent metal ions, particularly copper. PrP(C) has been suggested to be involved in copper transport and metabolism and in cell defense mechanisms against oxidative insult, possibly through the regulation of the intracellular CuZn superoxide dismutase activity (CuZn-SOD) or a SOD-like activity of PrP(C) itself. However, up to now the link between PrP(C) expression and copper metabolism or SOD activity has still to be formally established; particularly because conflicting results have been obtained in vivo. In this study, we report a link between PrP(C), copper binding, and resistance to oxidative stress. Radioactive copper ((64)Cu) was used at a physiological concentration to demonstrate that binding of copper to the outer plasma cell membrane is related to the level of PrP(C) expression in a cell line expressing a doxycycline-inducible murine PrP(C) gene. Cellular PIPLC pretreatment indicated that PrP(C) was not involved in copper delivery at physiological concentrations. We also demonstrated that murine PrP(C) expression increases several antioxidant enzyme activities and glutathione levels. Prion protein may be a stress sensor sensitive to copper and able to initiate, following copper binding, a signal transduction process acting on the antioxidant systems to improve cell defenses.
Rachidi
Walid
W
Laboratoire de Biologie du Stress Oxydant (LBSO), Faculté de Pharmacie, Domaine de La Merci, 38706 La Tronche-Grenoble cedex 9, France. walid.rachidi@ujf-grenoble.fr
Vilette
Didier
D
Guiraud
Pascale
P
Arlotto
Marie
M
Riondel
Jacqueline
J
Laude
Hubert
H
Lehmann
Sylvain
S
Favier
Alain
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D003300:Copper / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000378:metabolism / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D015227:Lipid Peroxidation; D008345:Manganese / Q000494:pharmacology; D051379:Mice; D008856:Microscopy, Fluorescence; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000378:metabolism; D018384:Oxidative Stress; D011328:Prions / Q000096:biosynthesis* / Q000502:physiology; D011485:Protein Binding; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000378:metabolism; D013997:Time Factors
D000975:Antioxidants; D011328:Prions; D008345:Manganese; C002385:linsidomine; D003300:Copper; D008981:Molsidomine; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione; D004318:Doxycycline