History and state of the art of PrP-res “typing” in Creutzfeldt-Jakob disease

Summary

Much progress has been made in understanding the molecular basis of phenotypic variability in Creutzfeldt-Jakob disease (CJD) in the last ten years. The most significant advance was the discovery that the genotype at polymorphic codon 129 of PRNP and the “type” of the protease-resistant prion protein fragment, PrP-res, have a major influence on the disease phenotype in all forms of CJD, irrespective of their etiology. The most widely accepted CJD classification includes six clinico-pathological phenotypes and two major types of PrP-res, types 1 and 2, which can be distinguished on the basis of a ∼2 kDa difference in relative molecular mass of the protein fragment. However, alternative classifications of human PrP-res types distinguished three patterns of PrP-res molecular mass instead of two, thereby creating significant confusion in the field. Fortunately, progress has been recently made in clarifying these disparities. Most significant in this regard, has been the finding that pH variation among CJD brain homogenates in standard buffers influences the size of PrP-res. Thus, some of the PrP-res heterogeneity used to identify putative strain-specific PrP-res types simply represents a technical “artefact” related to the experimental conditions. On the other hand, recent data have also shown that PrP-res types 1 and 2 are heterogeneous biological species, which can be further distinguished into molecular subtypes that fit the current histopathological classification of sporadic CJD in 6 subtypes. Finally, novel truncated PrP-res fragments of smaller size than PrP-res types 1 and 2 have recently been identified in CJD. Although more studies are needed to fully characterize the presence, characteristics and biological significance of these peptides, preliminary results indicate that their search and characterization may be useful in the molecular diagnostics of CJD subtypes.