Host Determinants of Prion Strain Diversity Independent of Prion Protein Genotype

Abstract

Phenotypic diversity in prion diseases can be specified by prion strains in which biological traits are propagated through an epigenetic mechanism mediated by distinct PrP Sc conformations. We investigated the role of host-dependent factors on phenotypic diversity of chronic wasting disease (CWD) in different host species that express the same prion protein gene (Prnp). Two CWD strains that have distinct biological, biochemical, and pathological features were identified in transgenic mice that express the Syrian golden hamster (SGH) Prnp. The CKY strain of CWD had a shorter incubation period than the WST strain of CWD, but after transmission to SGH, the incubation period of CKY CWD was ϳ150 days longer than WST CWD. Limited proteinase K digestion revealed strain-specific PrP Sc polypeptide patterns that were maintained in both hosts, but the solubility and conformational stability of PrP Sc differed for the CWD strains in a host-dependent manner. WST CWD produced PrP Sc amyloid plaques in the brain of the SGH that were partially insoluble and stable at a high concentration of protein denaturant. However, in transgenic mice, PrP Sc from WST CWD did not assemble into plaques, was highly soluble, and had low conformational stability. Similar studies using the HY and DY strains of transmissible mink encephalopathy resulted in minor differences in prion biological and PrP Sc properties between transgenic mice and SGH. These findings indicate that host-specific pathways that are independent of Prnp can alter the PrP Sc conformation of certain prion strains, leading to changes in the biophysical properties of PrP Sc , neuropathology, and clinical prion disease. IMPORTANCEPrions are misfolded pathogenic proteins that cause neurodegeneration in humans and animals. Transmissible prion diseases exhibit a spectrum of disease phenotypes and the basis of this diversity is encoded in the structure of the pathogenic prion protein and propagated by an epigenetic mechanism. In the present study, we investigated prion diversity in two hosts species that express the same prion protein gene. While prior reports have demonstrated that prion strain properties are stable upon infection of the same host species and prion protein genotype, our findings indicate that certain prion strains can undergo dramatic changes in biological properties that are not dependent on the prion protein. Therefore, host factors independent of the prion protein can affect prion diversity. Understanding how host pathways can modify prion disease phenotypes may provide clues on how to alter prion formation and lead to treatments for prion, and other, human neurodegenerative diseases of protein misfolding.

PrP C Governs Susceptibility to Prion Strains in Bank Vole, While Other Host Factors Modulate Strain Features

“…However, differences in brain PrP res Western blot profiles observed between the two animal models inoculated with the same inoculum support the hypothesis (34,35) that the genetic background can impact the strain features of the prion agent.…”

“…This suggests that during experimental transmissions involving a species barrier, additional host factors other than PrP C might have played a role in driving either the fidelity of prion replication or the selection of substrains being preferentially replicated in the new hosts. In a recent work, the transmission features of two strains of transmissible mink encephalopathy (TME) and two strains of chronic wasting disease (CWD) were compared in hamster species and in transgenic mice overexpressing hamster PrP (34). While the properties of TME strains were maintained in both hosts, the properties of CWD strains were different in hamsters and transgenic mice.…”

PrPSc-Specific Antibody Reveals C-Terminal Conformational Differences between Prion Strains

“…The existence of multiple prion strains within hosts of a given genotype implies that the phenotypic diversity of prions and PrP Sc can be maintained without variations in the primary structure of the constituent PrP molecules. Conversely, it is also true that a single prion strain replicating in hosts of different genotypes can have different biological properties (40,41). These observations provide evidence that PrP Sc conformational diversity is important in defining prion strains.…”

Prion Type-Dependent Deposition of PRNP Allelic Products in Heterozygous Sheep

“…In these spontaneous prion diseases, PrP C can be considered to be the main host factor determining the PrP allotype ratio of the prion material. However, the role of non-PrP host factors should also be taken into consideration (64). Under infectious conditions, such as those studied in animals, the agent itself can have an equally important role as that of host PrP and non-PrP host factors.…”