These two leading prion researchers both appear to be heading to the same finish line; at least their on the same track!!
Very interesting abstracts, considering that Dr. David Brown and Dr. BS Wong, et al. "found a decrease of up to 50% of copper and an increase in manganese of approximately 10-fold in the brain tissues from sCJD subjects." "Aberrant metal binding by prion protein in human prion disease. (2001)
kind of makes me feel all fuzzy and warm.
Very interesting abstracts, considering that Dr. David Brown and Dr. BS Wong, et al. "found a decrease of up to 50% of copper and an increase in manganese of approximately 10-fold in the brain tissues from sCJD subjects." "Aberrant metal binding by prion protein in human prion disease. (2001)
J Neurochem. 2006 Jun 19; [Epub ahead of print]
Prion protein reduces both oxidative and non-oxidative copper toxicity
Haigh CL, Brown DR.
Department of Biology and Biochemistry, University of Bath, Bath, UK.
The prion protein is a membrane tethered glycoprotein that binds copper. Conversion to an abnormal isoform is associated with neurodegenerative diseases known as prion diseases. Expression of the prion protein has been suggested to prevent cell death caused by oxidative stress. Using cell based models we investigated the potential of the prion protein to protect against copper toxicity. Although prion protein expression effectively protected neurones from copper toxicity, this protection was not necessarily associated with reduction in oxidative damage. We also showed that glycine and the prion protein could both protect neuronal cells from oxidative stress. Only the prion protein could protect these cells from the toxicity of copper. In contrast glycine increased copper toxicity without any apparent oxidative stress or lipid peroxidation. Mutational analysis showed that protection by the prion protein was dependent upon the copper binding octameric repeat region. Our findings demonstrate that copper toxicity can be independent of measured oxidative stress and that prion protein expression primarily protects against copper toxicity independently of the mechanism of cell death.
PMID: 16787422
Arch Virol. 2006 Jun 22; [Epub ahead of print]
Copper induces conformational changes in the N-terminal part of cell-surface PrP(C).
Leclerc E, Serban H, Prusiner SB, Burton DR, Williamson RA.
Department of Immunology, The Scripps Research Institute, La Jolla, CA, U.S.A..
Prion diseases are caused by misfolding of the cellular prion protein, PrP(C). In vitro studies have shown that PrP binds copper via the octarepeat region lying within the unstructured N-terminal segment of the protein, but the significance of copper in PrP metabolism remains unclear. Here, six specific antibodies recognizing different epitope regions of PrP were used to measure the effect of copper on the conformation of the molecule at the cell surface. Binding of an antibody, E149, to an epitope within the octarepeat domain of PrP is halved in the presence of copper, whereas binding of antibodies recognizing epitope motifs C-terminal to residue 90 of PrP remain relatively unaltered under equivalent conditions. These experiments strongly suggest that copper induces localized conformational change within the N-terminal portion of cell-surface PrP(C).
PMID: 16791441
kind of makes me feel all fuzzy and warm.