title: Amidation and structure relaxation abolish the neurotoxicity of the prion peptide PrP106-126 in vivo and in vitro.
abstract: One of the major pathological hallmarks of transmissible spongiform encephalopathies (TSEs) is the accumulation of a pathogenic (scrapie) isoform (PrP(Sc)) of the cellular prion protein (PrP(C)) primarily in the central nervous system. The synthetic prion peptide PrP106-126 shares many characteristics with PrP(Sc) in that it shows PrP(C)-dependent neurotoxicity both in vivo and in vitro. Moreover, PrP106-126 in vitro neurotoxicity has been closely associated with the ability to form fibrils. Here, we studied the in vivo neurotoxicity of molecular variants of PrP106-126 toward retinal neurons using electroretinographic recordings in mice after intraocular injections of the peptides. We found that amidation and structure relaxation of PrP106-126 significantly reduced the neurotoxicity in vivo. This was also found in vitro in primary neuronal cultures from mouse and rat brain. Thioflavin T binding studies showed that amidation and structure relaxation significantly reduced the ability of PrP106-126 to attain fibrillar structures in physiological salt solutions. This study hence supports the assumption that the neurotoxic potential of PrP106-126 is closely related to its ability to attain secondary structure.
authors.affiliation: Danish Institute for Food and Veterinary Research, Department of Veterinary Diagnostics and Research, Copenhagen. alb@dfvf.dk
authors.forename: Ann-Louise
authors.initials: AL
authors.lastname: Bergström
authors.forename: Henriette
authors.initials: H
authors.lastname: Cordes
authors.forename: Nicole
authors.initials: N
authors.lastname: Zsurger
authors.forename: Peter M H
authors.initials: PM
authors.lastname: Heegaard
authors.forename: Henning
authors.initials: H
authors.lastname: Laursen
authors.forename: Joëlle
authors.initials: J
authors.lastname: Chabry
mesh_terms: D000682:Amyloid / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D052160:Benzothiazoles; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D004596:Electroretinography; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D018621:PrPC Proteins / Q000737:chemistry* / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000502:physiology*; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins; D012160:Retina / Q000378:metabolism; D012492:Salts / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000737:chemistry; D013997:Time Factors
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D010455:Peptides; D018621:PrPC Proteins; D011328:Prions; D020033:Protein Isoforms; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012492:Salts; D013844:Thiazoles; C466227:miniprion protein PrP106, mouse; C009462:thioflavin T; D020169:Caspases; D010100:Oxygen