NR AUQO
AU Gilch,S.; Ertmer,A.; Schulz,G.; Kehler,C.; Maas,E.; Lutzny,G.; Krammer,C.; Bach,C.; Bruns,C.; Nunziante,M.; Vorberg,I.; Schätzl,H.M.
TI Strategies to eliminate PrPc as substrate for conversion into PrPsc
QU TSE-Forum, 6. Kongress - Nationale TSE-Forschungsplattform, Greifswald 26.6.-28.6.2006, Vortrag V-07
PT Konferenz-Vortrag
AB Prion diseases are fatal neurodegenerative infectious disorders for which no therapeutic or prophylactic regimens exist. Our work aims at eliminating PrPc as substrate for the conversion into PrPsc or at increasing the cellular clearance capacity for PrPsc. For the first purpose, we have used chemical compounds like Suramin and derivatives which interfere with the subcellular trafficking of PrPc by intracellular re-routing (Gilch et al., 2001; Nunziante et al., 2005). Recently, we found that PrPc requires cholesterol for cell surface localization. We show that the treatment with mevinolin significantly reduced the amount of cell-surface PrPc and led to its accumulation in the Golgi compartment. These data show that cholesterol is essential for the cell surface localisation of PrPc, which is, in turn, known to be necessary for PrPsc formation (Gilch et al., 2005). Another anti-prion strategy uses RNA and peptide aptamers directed against PrPc (Proske et al., 2002). We have selected now peptide aptamers using a constrained peptide library presented on the active-site loop of the E. coli protein TrxA in a Y2H screen employing full-length PrP as a bait. Several peptides reproducibly binding to PrPc in several assays were identified. Preliminary data indicate that selected peptide aptamers are able to interfere with prion propagation in prion infected cells. To obtain additive effects we have tried to elucidate cellular mechanisms which enable cells to clear prion infectivity. This goal was accomplished by selective interference in intracellular signalling pathways which apparently increase the cellular autophagy machinery (Ertmer et al., 2004). Finally, we have tried to establish an active auto-vaccination approach directed against PrP which provided some preliminary positive results in the mouse system (Gilch et al., 2003; Polymenidou et al., 2004). This might open the door towards classical immunological interference techniques.
AD Sabine Gilch, Alexa Ertmer, Gunnar Schulz, Claudia Kehler, Elke Maas, Gloria Lutzny, Carmen Krammer, Christian Bach, Christopher Bruns, Max Nunziante, Ina Vorberg and Hermann M. Schätzl, Institute of Virology, Technical University of Munich, Trogerstrasse 30, 81675 Munich, Germany
SP englisch
PO Deutschland
OR Tagungsband