Propagation of PrPSc in mice reveals impact of aggregate composition on prion disease pathogenesis.

Infectious prions consist of PrP^Sc, a misfolded, aggregation-prone isoform of the host's prion protein. PrP^Sc assemblies encode distinct biochemical and biological properties. They harbor a specific profile of PrP^Sc species, from small oligomers to fibrils in different ratios, where the highest infectivity aligns with oligomeric particles. To investigate the impact of PrP^Sc aggregate complexity on prion propagation, biochemical properties, and disease pathogenesis, we fractionated elk prions by sedimentation velocity centrifugation, followed by sub-passages of individual fractions in cervidized mice. Upon first passage, different fractions generated PrP^Sc with distinct biochemical, biophysical, and neuropathological profiles. Notably, low or high molecular weight PrP^Sc aggregates caused different clinical signs of hyperexcitability or lethargy, respectively, which were retained over passage, whereas other properties converged. Our findings suggest that PrP^Sc quaternary structure determines an initial selection of a specific replication environment, resulting in transmissible features that are independent of PrP^Sc biochemical and biophysical properties. Prion aggregate complexity affects prion biochemical properties, neuropathology, and clinical signs upon infection of mice. Aggregate size-specific clinical signs are retained upon passage despite convergence of prion properties. [ABSTRACT FROM AUTHOR]