Molecular classification of sporadic Creutzfeldt-Jakob disease

Abstract

According to the protein-only hypothesis of prion propagation, an abnormal isoform (designated PrPSc) of the cellular prion protein (PrPC) is the principal or sole component of transmissible prions. However, the existence of multiple prion strains has been difficult to accommodate within this hypothesis. We have previously reported the identification of four types of human PrPSc associated with sporadic and acquired human prion diseases. These PrPSc types are distinguished by differing molecular mass of fragments following limited proteinase K digestion and by differing ratios of di-, mono- and unglycosylated PrPSc. That these discrete biochemical features of PrPSc are serially transmissible to human PrP in transgenic mice following experimental transmission suggests that they may be responsible for encoding prion strain diversity. Here we present detailed clinical, pathological and molecular data from a large number of sporadic Creutzfeldt-Jakob disease (CJD) cases. We show that PrPSc types are associated with codon 129 status, duration of illness and neuropathological phenotype. A novel PrPSc type is presented, illustrating further heterogeneity in CJD, and suggesting that further molecular subtypes of CJD may exist at lower frequencies. A molecular classification of sporadic CJD is proposed.