title: Translocation of cellular prion protein to non-lipid rafts protects             human prion-mediated neuronal damage.
abstract: 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 association             of their glycosyl-phosphatidylinositol (GPI) anchor with saturated raft lipids             and interaction of their N-terminal regions. Our previous study showed that cellular             cholesterol enrichment prevented PrP(106-126)-induced neuronal death. We have             now studied the influence of membrane cholesterol in PrP(106-126)-mediated neurotoxicity             and identified membrane domains involved in this activity. We found that PrPC             is normally distributed in lipid rafts, but high membrane cholesterol levels as             a result of cholesterol treatment led to the translocation of PrPC from lipid             rafts to non-lipid rafts. Moreover, cholesterol-mediated PrPC translocation protects             PrP(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, translocation             of Bax and cytochrome c by prion protein fragment. Our results indicate that modulation             of the PrPC location appears to protect against neuronal cell death caused by             prion peptides. The results of this study suggest that regulation of membrane             cholesterol affects the translocation of PrPC, which in turn regulates PrP(106-126)-induced             mitochondrial dysfunction and neurotoxicity.
authors.affiliation: Korea Zoonoses Research Institute, Center for Healthcare Technology                     Development, College of Veterinary Medicine, Chonbuk National University,                     Jeonju, Jeonbuk 561-756, Republic of Korea.
authors.forename: Jae-Kyo
authors.initials: JK
authors.lastname: Jeong
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Moon
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Seol
authors.forename: Sang-Youel
authors.initials: SY
authors.lastname: Park
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology; D018621:PrPC Proteins / Q000378:metabolism*; D011328:Prions / Q000138:chemical synthesis / Q000494:pharmacology; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D010446:Peptide Fragments; D018621:PrPC Proteins; D011328:Prions; C082632:prion protein (106-126); D002784:Cholesterol