NR AOTC
AU Gilch,S.; Nunziante,M.; Schätzl,H.M.
TI Intracellular re-routing of prion protein aggregates is mediated by the pre-octarepeat domain of PrP
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - BR-57
PT Konferenz-Poster
AB Prion diseases are fatal and transmissible neurodegenerative disorders linked to an aberrant conformation of the cellular prion protein (PrPc). We showed that Suramin induced aggregation of PrP, prevented further trafficking of PrPc to the plasma membrane and inhibited the de novo generation of PrPsc in prion infected cells. Instead, misfolded PrP was re-routed to acidic compartments for degradation. The prophylactic potential of Suramin against prion infection in vivo was tested in mice. After intraperitoneal infection application of Suramin significantly delayed onset of prion disease. Using PrP deletion mutants we were able to show that intracellular re-routing but not aggregation is dependent on the presence of the N-terminal PrP (aa 23-90). The N-terminus of PrP can be roughly divided into two parts: the octarepeat domain (aa 51-91) and the highly conserved basically charged pre-octarepeat domain (aa 23-50). From our data we conclude that mainly the pre-octarepeat domain is responsible for intracellular re-routing. In the PrP paralogue Doppel is a corresponding region located between aa 27-50. After insertion of this part of Doppel into N-terminally deleted PrP the re-routing phenotype could be rescued. On the other hand, fusion of the PrP N-terminus to either Doppel or the non-related GPI-anchored protein Thy-I did not induce aggregation of these proteins upon Suramin treatment, arguing against two binding sites of Suramin to PrP. Our data reveal for the first time an important role of the basically charged pre-octarepeat region of PrP in controlling the trafficking of misfolded PrP.
AD S. Gilch, M. Nunziante, H.M. Schätzl, Institute for Virology, Technical University Munich, Germany
SP englisch
PO Deutschland