Oxidation reduces the fibrillation but not the neurotoxicity of the prion peptide PrP106-126.
There is increasing evidence that soluble oligomers of misfolded protein may play a role in the pathogenesis of protein misfolding diseases including the transmissible spongiform encephalopathies (TSE) where the protein involved is the prion protein, PrP. The effect of oxidation on fibrillation tendency and neurotoxicity of different molecular variants of the prion peptide PrP106-126 was investigated. It was found that methionine oxidation significantly reduced amyloid fibril formation and proteinase K resistance, but it did not reduce (but rather increase slightly) the neurotoxicity of the peptides in vivo (electroretinography after intraocular injections in mice) and in vitro (in primary neuronal cultures). We furthermore found that the bovine variant of PrP106-126, containing only one methionine residue, showed both reduced fibril forming capacity and in vivo and in vitro neurotoxicity. The findings imply (I) that there is not a simple relation between the formation of amyloid fibrils and neurotoxicity of PrP106-126 derived peptides, (II) that putative, soluble, non-amyloid protofibrils, presumed to be present in increased proportions in oxidized PrP106-126, could play a role in the pathogenesis of TSE and III) that the number of methionine residues in the PrP106-126 peptide seems to have a pivotal role in determining the physical and biological properties of PrP106-126.
Bergström
Ann-Louise
AL
National Veterinary Institute, Technical University of Denmark, Bülowsvej 27, 1790 Copenhagen V, Denmark. alb@vet.dtu.dk
Chabry
Joëlle
J
Bastholm
Lone
L
Heegaard
Peter M H
PM
D000682:Amyloid / Q000648:ultrastructure; D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D008715:Methionine / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity* / Q000648:ultrastructure; D011328:Prions / Q000737:chemistry* / Q000633:toxicity* / Q000648:ultrastructure
D000682:Amyloid; D009498:Neurotoxins; D010446:Peptide Fragments; D011328:Prions; C082632:prion protein (106-126); D008715:Methionine