Abstract
Prions are proteinaceous infectious agents responsible for fatal neurodegenerative diseases in animals and humans. They are essentially composed of PrPSc, an aggregated, misfolded conformer of the ubiquitously expressed host-encoded prion protein (PrPC). Stable variations in PrPSc conformation are assumed to encode the phenotypically tangible prion strains diversity. However the direct contribution of PrPSc quaternary structure to the strain biological information remains mostly unknown. Applying a sedimentation velocity fractionation technique to a panel of ovine prion strains, classified as fast and slow according to their incubation time in ovine PrP transgenic mice, has previously led to the observation that the relationship between prion infectivity and PrPSc quaternary structure was not univocal. For the fast strains specifically, infectivity sedimented slowly and segregated from the bulk of proteinase-K resistant PrPSc. To carefully separate the respective contributions of size and density to this hydrodynamic behavior, we performed sedimentation at the equilibrium and varied the solubilization conditions. The density profile of prion infectivity and proteinase-K resistant PrPSc tended to overlap whatever the strain, fast or slow, leaving only size as the main responsible factor for the specific velocity properties of the fast strain most infectious component. We further show that this velocity-isolable population of discrete assemblies perfectly resists limited proteolysis and that its templating activity, as assessed by protein misfolding cyclic amplification outcompetes by several orders of magnitude that of the bulk of larger size PrPSc aggregates. Together, the tight correlation between small size, conversion efficiency and duration of disease establishes PrPSc quaternary structure as a determining factor of prion replication dynamics. For certain strains, a subset of PrP assemblies appears to be the best template for prion replication. This has important implications for fundamental studies on prions.
Highlights
Prion disease pathogenesis stems from the post-translational conversion of the monomeric, alpha helix-rich host-encoded prion protein (PrPC) into misfolded, b sheet-enriched PrPSc aggregates [1]
We further showed that these small assemblies resist proteolytic digestion and outcompete by several orders of magnitude the larger-size assemblies in cell-free prion conversion assays
A discrete subset of PrPSc assemblies appears to be the best template for prion replication
Summary
Prion disease pathogenesis stems from the post-translational conversion of the monomeric, alpha helix-rich host-encoded prion protein (PrPC) into misfolded, b sheet-enriched PrPSc aggregates [1]. A variety of prion variants or strains exist within a given host species. They cause diseases with specific phenotypic traits, including time course to disease and neuropathological features. The conformational underpinnings of the prion strain phenomenon and notably the contribution of PrPSc quaternary structure remain largely elusive. These differences must be sufficiently local to allow faithful prion transmission at least within and between individuals of the same species. Non-PrP components might be part of prion infectious particle or act as a scaffold during the conversion and/or aggregation process and might contribute to prion strain biological phenotype (reviews: [3,19])
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