NR AUSE
AU Mitteregger,G.; Vosko,M.; Krebs,B.; Xiang,W.; Burk,J.; Kohlmannsperger,V.; Nölting,S.; Hamann,G.F.; Kretzschmar,H.A.
TI The role of the octarepeat region and its histidines in neuroprotective function of PrPc
QU TSE-Forum, 6. Kongress - Nationale TSE-Forschungsplattform, Greifswald 26.6.-28.6.2006, Poster: Pathogenese/Infektion PATH-05
PT Konferenz-Poster
AB A templated conformational transition of the cellular prion protein (PrPc) from a predominantly alpha-helical form to a ß-sheet rich isoform, the scrapie prion protein (PrPsc), seems to be the cause of transmissibility and pathogenesis of prion diseases such as BSE and Creutzfeldt-Jakob disease (CJD). To date, the physiological function of PrPc has been elusive. It seems to play a fundamental role in neuroprotection and oxidative stress reaction. Cell culture experiments have indicated that copper binding to the N-terminal octarepeat region of PrPc and cell signalling by the PI3K/Akt pathway may be important in this process. To investigate the physiological function of PrPc and the role of the PrPcoctarepeat in vivo, we used wild-type mice that synthesize normal PrPc, PrP knock-out (Prnp-/-) animals that are devoid of PrPc and transgenic mice that lack the octarepeat region (C4/- mice) and subjected them to controlled ischemia by middle cerebral artery occlusion (MCAO) and subsequent reperfusion. In ischemic brain areas we found increased expression of Prion protein gene in wild-type animals. In addition we identified increased degradation of PrPc. The infarct size in Prnp-/- animals was increased threefold when compared to wild-type animals. The infarct size in C4/- animals was identical to Prnp-/- mice, i.e. around three times larger than in wild-type mice. The prion protein in C4/- mice (PrPdelta32-93) therefore does not functionally rescue the Prnp-/- phenotype. It is quite clear from our experiments that the N-terminal copper binding octarepeat has a lead function in PrPc physiology and neuroprotection against oxidative stress in vivo. Additionally to elucidate the specific relevancy of the four copper binding sites of the octarepeat region in the neuroprotective function of PrPc, Prnp-/- mice were used for further investigations, expressing a murine octapeptide region with all four copper binding histidines replaced by glycines and these mice were compared with wild-type and Prnp-/- litter mates.
AD Gerda Mitteregger, Bjarne Krebs, Wei Xiang, Veronika Kohlmannsperger, Svenja Nölting1, Hans A. Kretzschmar, Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Feodor-Lynen-Str. 23, 81377 Munich, Germany; Milan Vosko, Jan Burk, Gerhard F. Hamann, Department of Neurology, Ludwig-Maximilians University, Klinikum Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany
SP englisch
PO Deutschland
EA Photo des in Greifswald gezeigten Posters, auf dem der Autor Jan Burk fehlt, Details
OR Tagungsband