Oxidized phosphatidylcholine formation and action in oligodendrocytes.
Reactive oxygen species play a major role in neurodegeneration. Increasing concentrations of peroxide induce neural cell death through activation of pro-apoptotic pathways. We now report that hydrogen peroxide generated sn-2 oxidized phosphatidylcholine (OxPC) in neonatal rat oligodendrocytes and that synthetic OxPC [1-palmitoyl-2-(5'-oxo)valeryl-sn-glycero-3 phosphorylcholine, POVPC] also induced apoptosis in neonatal rat oligodendrocytes. POVPC activated caspases 3 and 8, and neutral sphingomyelinase (NSMase) but not acid sphingomyelinase. Downstream pro-apoptotic pathways activated by POVPC treatment included the Jun N-terminal kinase proapoptotic cascade and the degradation of phospho-Akt. Activation of NSMase occurred within 1 h, was blocked by inhibitors of caspase 8, increased mainly C18 and C24:1 ceramides, and appeared to be concentrated in detergent-resistant microdomains (Rafts). We concluded that OxPC initially activated NSMase and converted sphingomyelin into ceramide to mediate a series of downstream pro-apoptotic events in oligodendrocytes.
Qin
Jingdong
J
Departments of Pediatrics, University of Chicago, Chicago, Illinois 60637, USA.
Testai
Fernando D
FD
Dawson
Sylvia
S
Kilkus
John
J
Dawson
Glyn
G
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010713:Phosphatidylcholines / Q000378:metabolism*; D010742:Phospholipid Ethers / Q000494:pharmacology; D051381:Rats
C400184:1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine; D010713:Phosphatidylcholines; D010742:Phospholipid Ethers; D006861:Hydrogen Peroxide