The prion strain phenomenon: molecular basis and unprecedented features

Abstract

Prions are unconventional infectious agents responsible for transmissible spongiform encephalopathies. Compelling evidences indicate that prions are composed exclusively by a misfolded form of the prion protein (PrP(Sc)) that replicates in the absence of nucleic acids. One of the most challenging problems for the prion hypothesis is the existence of different strains of the infectious agent. Prion strains have been characterized in most of the species. Biochemical characteristics of PrP(Sc) used to identify each strain include glycosylation profile, electrophoretic mobility, protease resistance, and sedimentation. In vivo, prion strains can be differentiated by the clinical signs, incubation period after inoculation and the lesion profiles in the brain of affected animals. Sources of prion strain diversity are the inherent conformational flexibility of the prion protein, the presence of PrP polymorphisms and inter-species transmissibility. The existence of the strain phenomenon is not only a scientific challenge, but it also represents a serious risk for public health. The dynamic nature and inter-relations between strains and the potential for the generation of a large number of new prion strains is the perfect recipe for the emergence of extremely dangerous new infectious agents.

Figure 1. PrP^Sc western blot profiles associated to different strains of human prions

Schematic representation of human PrP^Sc types after PK digestion. Particular polymorphic groups in position 129 are associated with specific PrP^Sc patterns. Types 1 and 2 are associated with sCJD, type 3 is mostly associated with iCJD and type 4 is found exclusively in vCJD.

Figure 2. Origin and properties of the HY and DY prion strains in hamsters

The Hyper (HY) and Drowsy (DY) scrapie strains were generated upon serial passage of transmissible mink encephalopathy (TME) infectious material in Syrian hamsters. The initial passage resulted in a very large incubation period that was upon successive passage stabilized in two different strains exhibiting strikingly different clinical, neuropathological, biochemical and infectious properties. The HY and DY hamster strains represent a prototype example of strain diversity without changes in amino acid sequence of the prion protein.