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.