Role of Lipid Rafts and GM1 in the Segregation and Processing of Prion Protein

The prion protein (PrP(C)) is highly expressed within the nervous system. Similar to other GPI-anchored proteins, PrP(C) is found in lipid rafts, membrane domains enriched in cholesterol and sphingolipids. PrP(C) raft association, together with raft lipid composition, appears essential for the conversion of PrP(C) into the scrapie isoform PrP(Sc,) and the development of prion disease. Controversial findings were reported on the nature of PrP(C)-containing rafts, as well as on the distribution of PrP(C) between rafts and non-raft membranes. We investigated PrP(C)/ganglioside relationships and their influence on PrP(C) localization in a neuronal cellular model, cerebellar granule cells. Our findings argue that in these cells at least two PrP(C) conformations coexist: in lipid rafts PrP(C) is present in the native folding (α-helical), stabilized by chemico-physical condition, while it is mainly present in other membrane compartments in a PrP(Sc)-like conformation. We verified, by means of antibody reactivity and circular dichroism spectroscopy, that changes in lipid raft-ganglioside content alters PrP(C) conformation and interaction with lipid bilayers, without modifying PrP(C) distribution or cleavage. Our data provide new insights into the cellular mechanism of prion conversion and suggest that GM1-prion protein interaction at the cell surface could play a significant role in the mechanism predisposing to pathology.