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Prions are the causative agents of transmissible spongiform encephalopathies,such as variant Creutzfeldt-Jakob disease in humans. Cellular prion proteins (PrPC)connect with cholesterol- and glycosphingolipid-rich lipid rafts through associationof their glycosyl-phosphatidylinositol (GPI) anchor with saturated raft lipidsand interaction of their N-terminal regions. Our previous study showed that cellularcholesterol enrichment prevented PrP(106-126)-induced neuronal death. We havenow studied the influence of membrane cholesterol in PrP(106-126)-mediated neurotoxicityand identified membrane domains involved in this activity. We found that PrPCis normally distributed in lipid rafts, but high membrane cholesterol levels asa result of cholesterol treatment led to the translocation of PrPC from lipidrafts to non-lipid rafts. Moreover, cholesterol-mediated PrPC translocation protectsPrP(106-126)-mediated apoptosis and p-38 activation and caspase-3 activation.In a mitochondrial functional assay including mitochondrial transmembrane potential,cholesterol treatment prevented the loss of mitochondrial potential, translocationof Bax and cytochrome c by prion protein fragment. Our results indicate that modulationof the PrPC location appears to protect against neuronal cell death caused byprion peptides. The results of this study suggest that regulation of membranecholesterol affects the translocation of PrPC, which in turn regulates PrP(106-126)-inducedmitochondrial dysfunction and neurotoxicity.

Translocation of cellular prion protein to non-lipid rafts protects human prion-mediated neuronal damage