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

Infectious prions consist of PrP, a misfolded, aggregation-prone isoform of the host's prion protein. PrP assemblies encode distinct biochemical and biological properties. They harbor a specific profile of PrP species, from small oligomers to fibrils in different ratios, where the highest infectivity aligns with oligomeric particles. To investigate the impact of PrP 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 with distinct biochemical, biophysical, and neuropathological profiles. Notably, low or high molecular weight PrP aggregates caused different clinical signs of hyperexcitability or lethargy, respectively, which were retained over passage, whereas other properties converged. Our findings suggest that PrP quaternary structure determines an initial selection of a specific replication environment, resulting in transmissible features that are independent of PrP biochemical and biophysical properties.