The prion protein requires cholesterol for cell surface localization

The cellular prion protein PrPc is attached to the plasma membrane by a glycosyl-phosphatidyl-inositol (GPI-) anchor and is localized in lipid rafts, membrane microdomains characterized by a high content of sphingolipids and cholesterol. Previous studies revealed that perturbation of cholesterol synthesis prevents prion conversion, explained by redistribution of PrPc at the plasma membrane. We investigated the influence of inhibition of cholesterol synthesis by the HMG-CoA-reductase inhibitor mevinolin on the trafficking of PrPc in neuronal cells. Treatment with mevinolin significantly reduces the amount of surface PrPc and leads to its accumulation in the Golgi compartment. Analysis of mutant PrPs highlights the importance of the GPI-anchor for raft localization and provides information about domains implicated in lipid raft association of PrP in the secretory pathway. Our data show that cholesterol is essential for the cell surface localization of PrPc, known to be necessary for prion conversion.