A receptor for infectious and cellular prion protein

Prions are an unconventional form of infectious agents composed only of pro tein and involved in transmissible spongiform encephalopathies in humans an d animals. The infectious particle is composed by PrPsc which is an isoform of a normal cellular glycosyl-phosphatidylinositol (GPI) anchored protein, PrPc, of unknown function. The two proteins differ only in conformation, P rPc is composed of 40% alpha helix while PrPsc has 60% beta-sheet and 20% a lpha helix structure. The infection mechanism is trigged by interaction of PrPsc with cellular prion protein causing conversion of the latter's confor mation. Therefore, the infection spreads because new PrPsc molecules are ge nerated exponentially from the normal PrPc. The accumulation of insoluble P rPsc is probably one of the events that lead to neuronal death. Conflicting data in the literature showed that PrPc internalization is mediated either by clathrin-coated pits or by caveolae-like membranous domains. However, b oth pathways seem to require a third protein (a receptor or a prion-binding protein) either to make the connection between the GPI-anchored molecule t o clathrin or to convert PrPc into PrPsc. We have recently characterized a 66-kDa membrane receptor which binds PrPc in vitro and in vivo and mediates the neurotoxicity of a human prion peptide. Therefore, the receptor should have a role in the pathogenesis of prion-related diseases and in the norma l cellular process. Further work is necessary to clarify the events trigger ed by the association of PrPc/PrPsc with the receptor.