NR AWJL
AU Malaise,M.E.L.; Brabeck,C.; Kloz,U.; Niemann,H.; Legler,D.; Groettrup,M.; Bürkle,A.
TI Roles of cellular prion protein in oxidative stress and mitochondrial function
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions CE-28
PT Konferenz-Poster
AB Despite being the subject of many recent studies, the physiological function of the cellular isoform of prion protein PrPc remains largely unresolved. Several candidate functions have been discussed, including binding and internalisation of copper or other metals, superoxide dismutase-like activity, regulation of cellular antioxidant activities and signal transduction. We have focussed on the TM1 region of PrPc (codons 110-135), due to its high conservation and the neurotoxicity of peptides derived from this region. To elucidate the physiological role of the PrPc TM1 domain in the context of the full-length PrPc molecule, we have constructed a set of deletion mutants centred on codons 114-121 of PrPc and mice expressing 114-121-PrP in different genetic backgrounds (Prnp+/+, Prnp+/-, Prnp-/-). Our aim is to elucidate a possible role of PrPc in anti-oxidative defence in cultured cells. For this purpose we have studied for the effect of overexpression of wt-PrP or 114-121-PrP in N2A mouse neuroblastoma cells on the intracellular level of reactive oxygen species (ROS). Endogenous ROS production was significantly lower in cells transfected with either wt or 114-121 expression plasmids. Furthermore the mitochondrial membrane potential ( was significantly lowered in wt-PrP or 114-121-PrP transfected cells. As PrPc can bind copper via its octarepeat region, we also tested the impact of copper on ROS level and Copper treatment leads to a decrease of in wt-PrP transfected cells, an increase of ROS level in 114-121-PrP transfected cells both under basal normal conditions and under exogenous oxidative stress. In order to perform analyses in a system closer to in vivo, we performed the same assays with primary brain cells derived from transgenic mice expressing 114-121-PrP in different genetic backgrounds (Prnp+/+, Prnp+/-, Prnp-/-). Our transgene seems to increase cellular sensitivity to oxidative stress. We conclude that PrPc plays a role in regulation, ROS level and oxidative stress sensitivity, mediated at least in part by the TM1 region.
AD M.E.L. Malaisé, C. Brabeck: Molecular Toxicology Group, Department of Biology, University of Konstanz, Germany; U. Kloz: Transgenic Core Facility, German Cancer Research Center, Heidelberg, Germany; H. Niemann: Division of Tumor Virology, German Cancer Research Center, Heidelberg, Germany; D. Legler, M. Groettrup: Immunology Group, Department of Biology, University of Konstanz; A. Bürkle: Molecular Toxicology Group, Department of Biology, University of Konstanz, Germany, and Division of Tumor Virology, German Cancer Research Center, Heidelberg, Germany E-mail: muriel.malaise@uni-konstanz.de
SP englisch
PO Italien