title: Involvement of the 5-lipoxygenase pathway in the neurotoxicity of the prion peptide PrP106-126.
abstract: Transmissible spongiform encephalopathies are characterised by the transformation of the normal cellular prion protein (PrP(C)) into an abnormal isoform (PrP(TSE)). Previous studies have shown that N-methyl-D-aspartate (NMDA) receptor antagonists can inhibit glutathione depletion and neurotoxicity induced by PrP(TSE) and a toxic prion protein peptide, PrP106-126, in vitro. NMDA receptor activation is known to increase intracellular accumulation of Ca(2+), resulting in up-regulation of arachidonic acid (AA) metabolism. This can stimulate the lipoxygenase pathways that may generate a number of potentially neurotoxic metabolites. Because of the putative relationship between AA breakdown and PrP106-126 neurotoxicity, we investigated AA metabolism in primary cerebellar granule neuron cultures treated with PrP106-126. Our studies revealed that PrP106-126 exposure for 30 min significantly up-regulated AA release from cerebellar granule neurons. PrP106-126 neurotoxicity was mediated through the 5-lipoxygenase (5-LOX) pathway, as shown by abrogation of neuronal death with the 5-LOX inhibitors quinacrine, nordihydroguaiaretic acid, and caffeic acid. These inhibitors also prevented PrP106-126-induced caspase 3 activation and annexin V binding, indicating a central role for the 5-LOX pathway in PrP106-126-mediated proapoptosis. Interestingly, inhibitors of the 12-lipoxygenase pathway had no effect on PrP106-126 neurotoxicity or proapoptosis. These studies clearly demonstrate that AA metabolism through the 5-LOX pathway is an important early event in PrP106-126 neurotoxicity and consequently may have a critical role in PrP(TSE)-mediated cell loss in vivo. If this is so, therapeutic intervention with 5-LOX inhibitors may prove beneficial in the treatment of prion disorders.
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria, Australia.
authors.forename: L R
authors.initials: LR
authors.lastname: Stewart
authors.forename: A R
authors.initials: AR
authors.lastname: White
authors.forename: M F
authors.initials: MF
authors.lastname: Jobling
authors.forename: B E
authors.initials: BE
authors.lastname: Needham
authors.forename: F
authors.initials: F
authors.lastname: Maher
authors.forename: J
authors.initials: J
authors.lastname: Thyer
authors.forename: K
authors.initials: K
authors.lastname: Beyreuther
authors.forename: C L
authors.initials: CL
authors.lastname: Masters
authors.forename: S J
authors.initials: SJ
authors.lastname: Collins
authors.forename: R
authors.initials: R
authors.lastname: Cappai
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000187:drug effects / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D002525:Cerebellar Cortex / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000633:toxicity*; D017096:Prion Diseases / Q000201:enzymology* / Q000503:physiopathology; D011328:Prions / Q000378:metabolism* / Q000633:toxicity*; D011796:Quinacrine / Q000494:pharmacology
chemical_list: D017304:Annexin A5; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D010446:Peptide Fragments; D011328:Prions; C082632:prion protein (106-126); D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D011796:Quinacrine; D008559:Memantine