NR AOYW
AU Schätzl,H.M.
TI Novel prophylactic and therapeutic approaches against prion infections
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Oral sessions OS-35
PT Konferenz-Vortrag
AB For prion diseases no effective prophylactic or therapeutic regimens are presently available. We focused initial experimental anti-prion efforts on compounds interfering with the surface expression of PrPc. We have extended this molecular strategy by introducing RNA aptamers and polyclonal antibodies directed against surface located PrPc or PrP folding intermediates. In order to induce auto-antibodies we used a murine PrP dimer expressed in E. coli. Using this immunogen we were able to effectively overcome auto-tolerance against murine PrP in wild-type mice without inducing obvious side effects. Treatment of prion-infected mouse cells with polyclonal anti-PrP auto-antibodies inhibited the endogenous PrPsc synthesis. Our data point to the possibility of developing means for an active immunoprophylaxis against prion diseases. Indeed, ongoing in vivo studies look promising. An alternative anti-prion approach came from recent work pointing to a possible role for PrP in signaling. In this context, we screened substances interfering in signaling pathways in prion-infected cells for effects on PrPsc propagation. We identified one compound which was highly effective in inhibition of PrPsc biogenesis. Prion-infected cells could be rapidly cured in a time- and dose-dependent manner, without effects on biogenesis and cellular trafficking of PrPc. The compound affects pre-existing PrPsc by reducing its half-life time, probably induced by functional up-regulation of lysosomal proteases. We demonstrated that these effects are caused by specific interference with the tyrosine-kinase c-abl. Our studies show that interference in specific intracellular signaling cascades can have impact on prion biogenesis and might provide novel targets for prophylaxis and therapy of prion diseases.
AD Hermann M Schätzl, Technical University of Munich, Germany
SP englisch
PO Deutschland