Prion protein peptides: optimal toxicity and peptide blockade of toxicity.
In prion disease neurodegeneration requires deposition of the abnormal isoform of the prion protein (PrP(Sc)) within nervous tissue. In vitro PrP(Sc) has neurotoxicity that can be mimicked by peptides based on part of its sequence. In this investigation the region of the protein required for maximal neurotoxicity was precisely determined. The optimal neurotoxic peptide was found to contain amino acids 112-126 of the human sequence. The sequence AGAAAAGA was found to be necessary but not sufficient for a neurotoxic effect. The AGAAAAGA peptide blocked the toxicity of PrP106-126, suggesting that this sequence is necessary for the interaction of PrP106-126 with neurons. These results suggest that targeting or use of the AGAAAAGA peptide may represent a therapeutic opportunity for controlling prion disease.
Brown
D R
DR
Department of Biochemistry, Cambridge University, Cambridge, CB2 1QW, United Kingdom.
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology* / Q000187:drug effects; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity*; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity* / Q000648:ultrastructure; D010455:Peptides / Q000633:toxicity*; D011328:Prions / Q000037:antagonists & inhibitors / Q000633:toxicity* / Q000648:ultrastructure; D011487:Protein Conformation
D009498:Neurotoxins; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; D011328:Prions; C082632:prion protein (106-126)