Beyond PrPres Type 1/Type 2 Dichotomy in Creutzfeldt-Jakob Disease

Abstract

Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K (PK) digested abnormal prion protein (PrP^res) identified on Western blotting (type 1 or type 2). These biochemically distinct PrP^res types have been considered to represent potential distinct prion strains. However, since cases of CJD show co-occurrence of type 1 and type 2 PrP^res in the brain, the basis of this classification system and its relationship to agent strain are under discussion. Different brain areas from 41 sCJD and 12 iatrogenic CJD (iCJD) cases were investigated, using Western blotting for PrP^res and two other biochemical assays reflecting the behaviour of the disease-associated form of the prion protein (PrP^Sc) under variable PK digestion conditions. In 30% of cases, both type 1 and type 2 PrP^res were identified. Despite this, the other two biochemical assays found that PrP^Sc from an individual patient demonstrated uniform biochemical properties. Moreover, in sCJD, four distinct biochemical PrP^Sc subgroups were identified that correlated with the current sCJD clinico-pathological classification. In iCJD, four similar biochemical clusters were observed, but these did not correlate to any particular PRNP 129 polymorphism or western blot PrP^res pattern. The identification of four different PrP^Sc biochemical subgroups in sCJD and iCJD, irrespective of the PRNP polymorphism at codon 129 and the PrP^res isoform provides an alternative biochemical definition of PrP^Sc diversity and new insight in the perception of Human TSE agents variability. Prion diseases are transmissible neurodegenerative disorders characterized by accumulation of an abnormal isoform (PrP^Sc) of a host-encoded protein (PrP^C) in affected tissues. According to the prion hypothesis, PrP^Sc alone constitutes the infectious agent. Sporadic Creutzfeldt-Jakob disease (sCJD) is the commonest human prion disease. Although considered as a spontaneous disorder, the clinicopathological phenotype of sCJD is variable and substantially influenced by the methionine/valine polymorphism at codon 129 of the prion protein gene (PRNP). Based on these clinicopathological and genetic criteria, a subclassification of sCJD has been proposed. Here, we used two new biochemical assays that identified four distinct biochemical PrP^Sc subgroups in a cohort of 41 sCJD cases. These subgroups correlate with the current sCJD subclassification and could therefore represent distinct prion strains. Iatrogenic CJD (iCJD) occurs following presumed accidental human-to-human sCJD transmission. Our biochemical investigations on 12 iCJD cases from different countries found the same four subgroups as in sCJD. However, in contrast to the sCJD cases, no particular correlation between the PRNP codon 129 polymorphism and biochemical PrP^Sc phenotype could be established in iCJD cases. This study provides an alternative biochemical definition of PrP^Sc diversity in human prion diseases and new insights into the perception of agent variability.