Distinct Stability States of Disease-Associated Human Prion Protein Identified by Conformation-Dependent Immunoassay

Abstract

The phenotypic and strain-related properties of human prion diseases are, according to the prion hypothesis, proposed to reside in the physicochemical properties of the conformationally altered, disease-associated isoform of the prion protein (PrP Sc ), which accumulates in the brains of patients suffering from Creutzfeldt-Jakob disease and related conditions, such as Gerstmann-Straussler-Scheinker disease. Molecular strain typing of human prion diseases has focused extensively on differences in the fragment size and glycosylation site occupancy of the protease-resistant prion protein (PrP res ) in conjunction with the presence of mutations and polymorphisms in the prion protein gene ( PRNP ). Here we report the results of employing an alternative strategy that specifically addresses the conformational stability of PrP Sc and that has been used previously to characterize animal prion strains transmitted to rodents. The results show that there are at least two distinct conformation stability states in human prion diseases, neither of which appears to correlate fully with the PrP res type, as judged by fragment size or glycosylation, the PRNP codon 129 status, or the presence or absence of mutations in PRNP . These results suggest that conformational stability represents a further dimension to a complete description of potentially phenotype-related properties of PrP Sc in human prion diseases.