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Prion diseases are associated with accumulation of strain-dependent biochemically distinct, disease-related isoforms (PrP(Sc)) of host-encoded prion protein (PrP(C)). PrP(Sc) is characterised by increased beta-sheet content, detergent insolubility and protease resistance. Recombinant alpha-PrP adopts a PrP(C)-like conformation, while beta-PrP conformationally resembles PrP(Sc), to these we raised 81 monoclonal antibodies in Prnp(0/0) mice. The N-terminal residues 91-110 are highly immunogenic in beta-PrP-immunised mice and of (17/41) anti-beta-PrP antibodies that could be epitope-mapped, approximately 70%, recognised this segment. In contrast, only 3/40 anti-alpha-PrP antibodies could be mapped and none interacted with this region, instead recognising residues 131-150, 141-160 and 171-190. Native PrP(C) was recognised by both antibody groups, but only anti-beta-PrP antibodies directed to 91-110 residues recognised native PrP(Sc) with high affinity, where in addition, species heterogeneity was also evident. Within the six anti-beta-PrP antibodies studied, they all recognised PK-treated native human and mouse PrP(Sc), four failed to recognise PK-treated native bovine PrP(Sc), one of which also did not recognise native PK-treated ovine PrP(Sc), showing the epitope becomes exposed on unfolding and disaggregation. These results demonstrate strain-dependent variations in chain conformation and packing within the 91-110 region of PrP(Sc).

Original publication

DOI

10.1016/j.bbapap.2007.08.028

Type

Journal article

Journal

Biochim Biophys Acta

Publication Date

11/2007

Volume

1774

Pages

1438 - 1450

Keywords

Animals, Antibodies, Monoclonal, Cattle, Epitope Mapping, Humans, Mice, Peptide Fragments, PrPC Proteins, PrPSc Proteins, Protein Conformation, Sheep, Species Specificity