NR AOXC
AU Mouthon,F.; Sturny,A.; Nouvel,V.; Deslys,J.P.
TI Intercellular Transfer of the Prion Protein : a New Strategy to Eludicate the Physiological Function of PrPc and Prion Propagation
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - BR-77
PT Konferenz-Poster
AB
Prion diseases are fatal neurodegenerative diseases that involve misfolding of the prion protein (PrP). Normal host PrP is bound to the external surface of the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor. Although the mechanism of PrP misfolding is not clear, this process may occure either at the cell surface or at some point during the endocytic trafficking.
We have studied the membrane properties of the normal PrP anchored by a GPI. Using a cell line overexpressing PrP and flow cytometry techniques, we have demonstrated the intercellular transfer of this GPI protein during direct cell to cell contact from the outer layer of the plasma membrane of one cell to another cell. This energy dependant intercellular transfer is specific of GPI anchorage and is inhibited by an enzymatic treatment which removes the GPI anchor.
Several lines of evidence suggest a role for rafts in formation of PrPres and recent studies indicated a modification of raft organization by amphotericin B treatment, which was previously described to interfere with prion replication. In our experiment, we observed a stabilisation of the PrP anchored at the plasma membrane after amphotericin B treatment in a dose dependant manner and a decrease of its availability for intercellular exchanges.
Currently available data suggest that PrPc might be implicated in neuronal architecture and survival but its function still remains unclear. Lastly, by using a PrPc defective cell line, we can reconstitute at the membrane surface the wild type expression of PrPc. Acquisition of PrP-GPI confers to PrPc defective cell line, protection from cell death after specific oxidative stress expositions.
This phenomenon of intercellular transfer of the PrP constitutes a new insight in the molecular biology of this protein. The use of engineered PrP-GPI offers new perspectives for the comprehension of physiological functions of PrP, prion dissemination and therapeutic strategies.
AD F. Mouthon, A. Sturny, V. Nouvel, J.P. Deslys, CEA/DSV/DRM/GIDTIP France
SP englisch
PO Deutschland