title: Squalestatin cures prion-infected neurons and protects against prion neurotoxicity.
abstract: A key feature of prion diseases is the conversion of the normal, cellular prion protein (PrP(C)) into beta-sheet-rich disease-related isoforms (PrP(Sc)), the deposition of which is thought to lead to neurodegeneration. In the present study, the squalene synthase inhibitor squalestatin reduced the cholesterol content of cells and prevented the accumulation of PrP(Sc) in three prion-infected cell lines (ScN2a, SMB, and ScGT1 cells). ScN2a cells treated with squalestatin were also protected against microglia-mediated killing. Treatment of neurons with squalestatin resulted in a redistribution of PrP(C) away from Triton X-100 insoluble lipid rafts. These effects of squalestatin were dose-dependent, were evident at nanomolar concentrations, and were partially reversed by cholesterol. In addition, uninfected neurons treated with squalestatin became resistant to the otherwise toxic effect of PrP peptides, a synthetic miniprion (sPrP106) or partially purified prion preparations. The protective effect of squalestatin, which was reversed by the addition of water-soluble cholesterol, correlated with a reduction in prostaglandin E(2) production that is associated with neuronal injury in prion disease. These studies indicate a pivotal role for cholesterol-sensitive processes in controlling PrP(Sc) formation, and in the activation of signaling pathways associated with PrP-induced neuronal death.
authors.affiliation: Institute of Comparative Medicine, Department of Veterinary Pathology, University of Glasgow Veterinary School, Bearsden Road, Glasgow G61 1QH, United Kingdom. c.bate@vet.gla.ac.uk
authors.forename: Clive
authors.initials: C
authors.lastname: Bate
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.forename: Luisa
authors.initials: L
authors.lastname: Diomede
authors.forename: Alun
authors.initials: A
authors.lastname: Williams
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D015850:Interleukin-6 / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000378:metabolism; D008954:Models, Biological; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D017830:Octoxynol / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry; D018621:PrPC Proteins / Q000737:chemistry*; D018620:PrPSc Proteins / Q000737:chemistry*; D011328:Prions / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014233:Tricarboxylic Acids / Q000494:pharmacology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003902:Detergents; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D010455:Peptides; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D017830:Octoxynol; D002784:Cholesterol; D015232:Dinoprostone; D008798:Mevalonic Acid