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

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) identified on Western blotting (type 1 or type 2). These biochemically distinct PrP 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 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 and two other biochemical assays reflecting the behaviour of the disease-associated form of the prion protein (PrP) under variable PK digestion conditions. In 30% of cases, both type 1 and type 2 PrP were identified. Despite this, the other two biochemical assays found that PrP from an individual patient demonstrated uniform biochemical properties. Moreover, in sCJD, four distinct biochemical PrP 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 pattern. The identification of four different PrP biochemical subgroups in sCJD and iCJD, irrespective of the PRNP polymorphism at codon 129 and the PrP isoform provides an alternative biochemical definition of PrP diversity and new insight in the perception of Human TSE agents variability. Citation: Uro-Coste E, Cassard H, Simon S, Lugan S, Bilheude J-M, et al. (2008) Beyond PrP Type 1/Type 2 Dichotomy in Creutzfeldt-Jakob Disease. PLoS Pathog 4(3): e1000029. doi:10.1371/journal.ppat.1000029 Editor: David Westaway, University of Alberta, Canada Received September 14, 2007; Accepted January 7, 2008; Published March 14, 2008 Copyright: 2008 Uro-Coste et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was financially supported by the ‘‘GIS prion’’ (French Research Ministry) and the Midi-Pyrénées Region. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] . These authors contributed equally to this work.