Squalestatin Cures Prion-infected Neurons and Protects Against Prion Neurotoxicity

A key feature of prion diseases is the conversion of the normal, cellular prion protein (PrPC) into β-sheet-rich disease-related isoforms (PrPSc), the deposition of which is thought to lead to neurodegeneration. In the present study, the squalene synthase inhibitor squalestatin reduced the cholester...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-04, Vol.279 (15), p.14983-14990
Main Authors: Bate, Clive, Salmona, Mario, Diomede, Luisa, Williams, Alun
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
Cell Line, Tumor
Cell Survival
Cells, Cultured
Cholesterol - metabolism
Detergents - pharmacology
Dinoprostone - metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
Enzyme-Linked Immunosorbent Assay
Interleukin-6 - metabolism
Membrane Microdomains - metabolism
Mevalonic Acid - pharmacology
Mice
Microglia - metabolism
Models, Biological
Neuroblastoma - metabolism
Neurons - metabolism
Octoxynol - pharmacology
Peptides - chemistry
Prions - metabolism
PrPC Proteins - chemistry
PrPSc Proteins - chemistry
Signal Transduction
Time Factors
Tricarboxylic Acids - pharmacology
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Summary:A key feature of prion diseases is the conversion of the normal, cellular prion protein (PrPC) into β-sheet-rich disease-related isoforms (PrPSc), 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 PrPSc 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 PrPC 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 E2 production that is associated with neuronal injury in prion disease. These studies indicate a pivotal role for cholesterol-sensitive processes in controlling PrPSc formation, and in the activation of signaling pathways associated with PrP-induced neuronal death.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M313061200