Cholesterol esterification reduces the neurotoxicity of prions.
The transmissible spongiform encephalopathies develop following the conversion of a host-encoded protein (PrP(C)) into abnormally folded, disease-related isoforms (PrP(Sc)). Here we report that three acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors, TMP-153, FR179254 or YIC-C8-434, were more toxic to prion-infected neuronal cell lines (ScGT1 and ScN2a cells) than to their uninfected equivalents (GT1 and N2a cells). The toxicity of ACAT inhibitors for ScGT1 cells was not reversed by the addition of cholesterol esters, rather it was increased by the addition of free cholesterol indicating that the toxicity of ACAT inhibitors was related to the increased free cholesterol content of cells rather than reduced amounts of cholesterol esters. This hypothesis was strengthened by the observation that the addition of free cholesterol killed ScGT1, but not GT1 cells. Treatment with ACAT inhibitors increased caspase-3 activity and prostaglandin E(2) production in ScGT1 cells but not in GT1 cells. The addition of the phospholipase A(2) (PLA(2)) inhibitors (AACOCF(3) or MAFP) reduced prostaglandin E(2) production and protected ScGT1 cells against the toxicity of ACAT inhibitors. These results indicate that cholesterol esterification is an important cellular response that reduces PrP(Sc)-induced activation of PLA(2) and protects against cell death in ScGT1 cells.
Bate
Clive
C
Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, UK. cbate@rvc.ac.uk
Tayebi
Mourad
M
Williams
Alun
A
D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D002934:Cinnamates / Q000627:therapeutic use*; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D018696:Neuroprotective Agents; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D054467:Phospholipases A2 / Q000096:biosynthesis; D010879:Piperazines / Q000627:therapeutic use*; D017096:Prion Diseases / Q000473:pathology / Q000517:prevention & control*; D011328:Prions / Q000187:drug effects*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
C440193:(N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine); D002934:Cinnamates; D004791:Enzyme Inhibitors; C111613:FR 179254; D018696:Neuroprotective Agents; D010671:Phenylurea Compounds; D010879:Piperazines; D011328:Prions; C088280:N-(4-(2-chlorophenyl)-6,7-dimethyl-3-quinolyl)-N'-(2,4-difluorophenyl)urea; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D054467:Phospholipases A2; D053148:Caspase 3; D015232:Dinoprostone