NR AOXB
AU Morot-Gaudry-Talarmain,Y.; Rezaei,H.; Guermonprez,L.; Treguer,E.; Grosclaude,J.
TI PrP cross-talk with cholinergic synaptic components is altered by oxidative stress
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - BR-101
PT Konferenz-Poster
AB
Cellular prion protein (PrPc) may play a neuroprotective function in participating in the redox control of neuronal environment and metabolic regulation of copper, a metal required for normal synaptic transmission and also a mild oxidative agent. Oxidative stress with peroxynitrite production was reported to develop in scrapie infected neurons, affecting choline acetyltransferase activity. In prion pathologies PrPc itself is modified into PrPsc and its potential partners may be altered by oxidative stress. The network of interactions underlying PrP function might thus be modified enhancing cellular dysfunctioning. To get insight into oxidative stress induced perturbations of cellular PrPc partners in cholinergic neurons we used a model in vitro system composed of nerve endings isolated from Torpedo marmorata as a donor of presynaptic components, peroxynitrite and copper treatments as a source of artificial oxidative stress and recombinant PrP protein as a ligand. Chemical modifications were analysed in Western blot by specific antibodies directed to the main synaptic components and to altered aminoacid residues (nitrosocysteine, nitrotyrosine).PrP/synaptic components specific interactions were followed on Biacore in conditions where immobilized PrP was not oxidized.
Peroxynitrite treatment abolished interaction in a concentration dependant way and induced significant alterations of neuronal targets.Cu2+ treatment triggered a milder oxidative effect leading to a bell-shape increase of PrP binding to synaptosomal components, counteracted by natural thiol agents as glutathione and thioredoxin. A positive correlation was pointed out between evolution of PrP binding and modifications of well-identified synaptic components, suggesting an original synergy with PrP for copper regulation. Our in vitro data show that PrP is able to recognize selective peroxynitrite and copper-mediated post translational modifications in neuronal targets. If these signatures are also recognized by PrP in vivo they may play a role in PrP trafficking in pathological conditions.
AD H. Rezaei, E. Treguer, J. Grosclaude, Virologie et Immunologie Moléculaires, INRA, France; Y. Morot-Gaudry-Talarmain, L. Guermonprez, Laboratory of Cellular and Molecular Neurobiology, CNRS, France
SP englisch
PO Deutschland