NR ARCU
AU Herms,J.W.; Vassallo,N.; Behrens,C.; Krebs,B.; Windl,O.; Kretzschmar,H.A.
TI Prion protein signaling through phosphatidylinositol 3-kinase
QU TSE-Forum, 4. Kongress - Nationale TSE-Forschungsplattform, Düsseldorf 28.10.-29.10.2004, Vortrag V-11
PT Konferenz-Vortrag
AB The exact biological role of the cellular prion protein (PrPc) remains to be established. Our aim in the present work was to gain insight into the physiological function of the molecule by looking at the relationship between copper binding, signaling, and cytoprotective roles of PrPc. Herein we report that, in mouse neuroblastoma N2a cells, PrPc activates phosphatidylinositol 3-kinase (PI 3-kinase) in a manner dependent on copper binding to the N-terminal octapeptide repeats of PrPc. Levels of PI 3-kinase activity were also found to be significantly lower in brain lysates from prion protein knockout mice, as compared to wild-type. Moreover, recruitment of PI 3-kinase by PrPc enhances cellular survival toward oxidative stress by 3-morpholinosydnonimine (SIN-1), which generates superoxide and peroxynitrite ions, but not to copper ions. Thus, we propose a model in which the interaction of copper(II) with the N-terminal domain of PrPc would activate the protein and induce a signal to PI 3-kinase; the latter, in turn, mediates downstream regulation of cell survival. A better understanding of the PrPc/PI 3-kinase pathway and how it affects neuronal survival may ultimately lead to novel approaches for treatment of prion diseases.
AD Jochen Herms1, Bjarne Krebs1, Hans Kretzschmar, Zentrum für Neuropathology und Prionforschung, Universität München, Germany; Neville Vassallo, Department of Physiology and Biochemistry, University of Malta, Msida MSD 06, Malta; Christina Behrens, Institut für Neuropathologie, Georg August Universität Göttingen, Germany; Otto Windl, 4TSE Molecular Biology, Veterinary Laboratories Agency, Weybridge Woodham Lane, Surrey KT15 3NB, United Kingdom
SP englisch
PO Deutschland
OR Tagungsband