NR AOQR
AU Brazier,M.W.; Volitakis,I.; Lawson,V.A.; Hill,A.F.; Masters,C.L.; Collins,S.J.
TI Effects of copper and manganese chelation therapy on the pathogenesis of a mouse model of prion disease
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - IV-15
PT Konferenz-Poster
AB Although the normal physiologic function of the prion protein (PrPc) has yet to be determined, many studies have demonstrated that PrPc is able to bind copper with high affinity. Recent in vitro and in vivo investigations have implicated manganese in the conversion process of PrPc to its protease resistant, pathogenic isoform PrPsc. Here we present our findings from a study where we trialled metal chelators as potential therapeutic strategies for prion infection. Using a well-characterised mouse model of prion infection, we have tested whether copper and manganese chelators have an effect on the disease incubation period. The copper chelator, clioquinol, chosen due to its proven efficacy in clearing insoluble A-beta plaques in an Alzheimer's disease model, was administered by gastric lavage feeding to mice. A manganese chelator, cyclohexanediaminetetraacetic acid (CDTA), was administered intaperitoneally. Both drugs were given to groups of mice treated early and late in the incubation period and the drugs were well tolerated. We found that none of the treatment groups, of either chelator, had any significant difference in the incubation period. However, CDTA was shown by ICP-MS to have reduced brain manganese levels by approximately 50%. Additionally, the brains of the CDTA treated mice harboured PrPsc that was markedly less protease resistant than that of untreated clinically affected mice. Treatment of PrPsc-containing brain homogenates with CDTA in vitro was also found to reduce the protease resistance of PrPsc. These results suggest that manganese may play a role in promoting and/or stabilising the conformation of the protease resistant isoform of the prion protein and that reduction of brain manganese levels, although perhaps not directly ameliorating disease, may provide an avenue for future therapeutic interventions in prion diseases.
AD M.W. Brazier, V.A. Lawson1, A.F. Hill, C.L. Masters, S.J. Collins, Department of Pathology, University of Melbourne, Victoria, Australia 3010; I. Volitakis, Mental Health Research Institute, Parkville, Victoria, Australia 3010; A.F. Hill, Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria, Australia 3010; S.J. Collins, Australian National Creutzfeldt-Jakob Disease Registry, University of Melbourne, Victoria, Australia 3010
SP englisch
PO Deutschland