NR AURY
AU Maas,E.; Kehler,C.; Krammer,C.; Schätzl,H.M.; Nunziante,M.
TI N-terminally truncated prion proteins display aberrant metabolism and can be converted into protease resistant isoforms in prion infected cells
QU TSE-Forum, 6. Kongress - Nationale TSE-Forschungsplattform, Greifswald 26.6.-28.6.2006, Poster: Struktur und zellbiologische Ansätze ZELL-04
PT Konferenz-Poster
AB
The exact domains within the prion protein (PrP) sequence necessary for the function of the cellular PrPc or for the conversion into its pathogen isoform (PrPsc) are not completely characterised. While mice devoid of PrPc develop normally and are resistant to prion infection, expression of PrP molecules presenting extended N-terminal deletions (amino acid 32-121 or 32-134) causes ataxia and neuronal loss in PrP knock-out mice. This phenotype can be rescued by co-expression with the wild type prion protein. In order to characterise the cell biological mechanisms underlying these events, PrP-constructs presenting similar extended deletions within the N-terminus were expressed in a cell culture model. The influence of these missing segments on PrP-function, trafficking and conversion into PrPsc was investigated.
The deleted PrP-mutants seemed to localise at the cell surface and also strongly in intracellular compartments (mainly in the Golgi and in lysosomes) and showed an alteration of the glycosylation and aggregation pattern. The mutated proteins also formed co-aggregates with endogenous wild-type PrP. In prion infected cells, only specific glycoforms of the truncated proteins were converted into PK resistant forms and their expression had a strong dominant negative effect on endogenous PrPsc.
These results show that the PrP N- terminal segments to amino acid 121 or 134 influence the biochemical properties and intracellular localisation of PrPc and affect formation of exogenous and endogenous protease resistant PrP. The interactions between wild-type and mutated molecules might help to elucidate the toxic phenotype seen in vivo.
AD Elke Maas, Claudia Kehler, Carmen Krammer, Hermann M. Schätzl and Max Nunziante, Institute of Virology, Technical University of Munich, Trogerstrasse 30, 81675 Munich, Germany
SP englisch
PO Deutschland
OR Tagungsband