Lack of prion protein expression results in a neuronal phenotype sensitive to stress.
The prion protein is a highly conserved glycoprotein expressed most highly in the synapse. Evidence has recently been put forward to suggest that the prion protein is an antioxidant. However, the functional importance of the prion protein has been disputed; it is claimed that mice genetically ablated to lack prion protein expression are normal and have no specific phenotype. We have reexamined the phenotype of prion protein knockout mice and found that there are multiple biochemical changes in the mice, including increased levels of nuclear factor NF-kappaB and Mn superoxide dismutase, COX-IV decreased levels of Cu/Zn superoxide dismutase activity, decreased p53, and altered melatonin levels. Additionally, cultured cells from these mice are more sensitive to a range of insults, all linked to increased neuronal sensitivity to oxidative stress. These results imply that prion protein knockout mice are more sensitive to oxidative stress and have an altered phenotype that must be taken into account when considering the additional effects of increased levels of proteins such as Doppel. The implication of these results is that the consequence of genetic ablation of genes must include biochemical analysis as well as analyses of possible developmental and behavioral changes.
Brown
David R
DR
Department of Biochemistry, Cambridge University, Cambridge, United Kingdom. bsscirb@bath.ac.uk
Nicholas
Richard St J
RS
Canevari
Laura
L
D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D008550:Melatonin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D010641:Phenotype; D011188:Potassium / Q000494:pharmacology; D018621:PrPC Proteins / Q000172:deficiency* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D056741:Cyclin D; D016213:Cyclins; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D016877:Oxidants; D018621:PrPC Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases; D008550:Melatonin; D011188:Potassium