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Prions are proteinaceous infectious agents responsible for fatal neurodegenerative diseases in animals and humans. They are essentially composed of PrP Sc , an aggregated, misfolded conformer of the ubiquitously expressed host-encoded prion protein (PrP C ). Stable variations in PrP Sc  conformation are assumed to encode the phenotypically tangible prion strains diversity. However the direct contribution of PrP Sc  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 PrP Sc  quaternary structure was not univocal. For the  fast  strains specifically, infectivity sedimented slowly and segregated from the bulk of proteinase-K resistant PrP Sc . 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 PrP Sc  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 PrP Sc  aggregates. Together, the tight correlation between small size, conversion efficiency and duration of disease establishes PrP Sc  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.

Quaternary Structure of Pathological Prion Protein as a Determining Factor of Strain-Specific Prion Replication Dynamics