Role of post‐translational modifications in prion strain diversity

Prion diseases are caused by the post‐translational conversion of the cellular prion protein (PrP C ) into a pathogenic β‐sheet rich misfolded isoform (PrP Sc ) that accumulates mainly in the brain. Prions can misfold into a wide variety of PrP Sc conformations, known as strains, that correlate to diverse biochemical properties and result in distinctive disease phenotypes, including differences in incubation times, clinical signs, histopathological lesion profiles, and PrP Sc deposition patterns in the brain within the same host genotype. Post‐translational modifications in PrP C include two N‐linked glycans and a glycophosphatidylinositol (GPI) anchor that may increase the conformational spectrum of PrP Sc . Previous studies have shown that passage of GPI‐anchored prion oligomers into mice expressing GPI‐anchorless PrP C switches the prion morphology from diffuse aggregates to dense, fibrillar plaques, yet it is unclear whether the original prion conformation is maintained within the anchorless PrP Sc fibrils. Here we aim 1) to determine the impact of the GPI‐anchorless state on the properties of the prion strain and 2) to identify the properties of the original GPI‐anchored prions that are maintained within the GPI‐anchorless fibril. We compared the biological, histological, and biochemical properties of four prion strains before and after three serial passages through mice expressing GPI‐anchorless PrP C . We found that the four GPI‐anchorless prion strains seemed to converge into a similar strain, as mice showed equivalent incubation periods and morphologically‐identical vasotropic fibrillar plaques in the brain. However, remarkable biochemical differences reminiscent of their respective original GPI‐anchored strains were also identified among anchorless prions. Interestingly, when passaged back into wild type mice expressing GPI‐anchored PrP C , some GPI‐anchorless prions recovered the properties from their original GPI‐anchored strain, indicating prion conformational fidelity. In contrast, other anchorless prions changed their properties markedly, consistent with the emergence of a new strain. Considering that GPI‐anchorless PrP C is normally present at low levels in the brain, these data suggest that alternate post‐translationally modified PrP C states may be a source of prion strain diversity within an individual. Support or Funding Information NIH grant R01NS069566