NR ASNZ
AU Bergström,A.L.; Cordes,H.; Zsurger,N.; Heegaard,P.M.H.; Laursen,H.; Chabry,J.
TI Amidation and structure relaxation abolish the neurotoxicity of the prion peptide PrP106-126 in vivo and in vitro
QU The Journal of Biological Chemistry 2005 Jun 17; 280(24): 23114-21
PT journal article
AB One of the major pathological hallmarks of transmissible spongiform encephalopathies (TSEs) is the accumulation of a pathogenic (scrapie) isoform (PrPsc) of the cellular prion protein (PrPc) primarily in the central nervous system. The synthetic prion peptide PrP106-126 shares many characteristics with PrPsc in that it shows PrPc-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.
MH Amyloid/chemistry; Animals; Apoptosis; Caspases/metabolism; Cell Survival; Cells, Cultured; Cerebellum/metabolism; Electroretinography; Immunohistochemistry; In Situ Nick-End Labeling; In Vitro; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons/metabolism; Oxygen/metabolism; Peptides/chemistry; PrPc Proteins/*chemistry/metabolism; Prions/*chemistry/*physiology; Protein Binding; Protein Conformation; Protein Isoforms; Protein Structure, Secondary; Protein Structure, Tertiary; RNA, Messenger/metabolism; Rats; Retina/metabolism; Salts/pharmacology; Spectrometry, Fluorescence; Thiazoles/chemistry; Time Factors
AD Danish Institute for Food and Veterinary Research, Department of Veterinary Diagnostics and Research, Copenhagen. alb@dfvf.dk
SP englisch
PO USA