Insights into the physiological function of cellular prion protein

Prions have been extensively studied since they represent a new class of in fectious agents in which a protein, PrPsc (prion scrapie), appears to be th e sole component of the infectious particle. They are responsible for trans missible spongiform encephalopathies, which affect both humans and animals. The mechanism of disease propagation is well understood and involves the i nteraction of PrPsc with its cellular isoform (PrPc) and subsequently abnor mal structural conversion of the latter. PrPc is a glycoprotein anchored on the cell surface by a glycosylphosphatidylinositol moiety and expressed in most cell types but mainly in neurons, Prion diseases have been associated with the accumulation of the abnormally folded protein and its neurotoxic effects; however, it is not known if PrPc loss of function is an important component. New efforts are addressing this question and trying to character ize the physiological function of PrPc. At least four different mouse strai ns in which the PrP gene was ablated were generated and the results regardi ng their phenotype are controversial. Localization of PrPc on the cell memb rane makes it a potential candidate fur a ligand uptake, cell adhesion and recognition molecule or a membrane signaling molecule. Recent data have sho wn a potential role for PrPc in the metabolism of copper and moreover that this metal stimulates PI Pe endocytosis, Our group has recently demonstrate d that PrPc is a high affinity laminin ligand and that this interaction med iates neuronal cell adhesion and neurite extension and maintenance, Moreove r, PrPc-caveolin-1 dependent coupling seems to trigger the tyrosine kinase Fyn activation. These data provide the first evidence fur PrPc involvement in signal transduction.