Biochemical Properties of Highly Neuroinvasive Prion Strains

Abstract

Infectious prions propagate from peripheral entry sites into the central nervous system (CNS), where they cause progressive neurodegeneration that ultimately leads to death. Yet the pathogenesis of prion disease can vary dramatically depending on the strain, or conformational variant of the aberrantly folded and aggregated protein, PrPSc. Although most prion strains invade the CNS, some prion strains cannot gain entry and do not cause clinical signs of disease. The conformational basis for this remarkable variation in the pathogenesis among strains is unclear. Using mouse-adapted prion strains, here we show that highly neuroinvasive prion strains primarily form diffuse aggregates in brain and are noncongophilic, conformationally unstable in denaturing conditions, and lead to rapidly lethal disease. These neuroinvasive strains efficiently generate PrPSc over short incubation periods. In contrast, the weakly neuroinvasive prion strains form large fibrillary plaques and are stable, congophilic, and inefficiently generate PrPSc over long incubation periods. Overall, these results indicate that the most neuroinvasive prion strains are also the least stable, and support the concept that the efficient replication and unstable nature of the most rapidly converting prions may be a feature linked to their efficient spread into the CNS.

Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping

“…3A). Similar strain plasticity has been observed in other neurodegenerative diseases (1,27,28,(33)(34)(35)(36). Considering the quite different and more malleable appearance of the hSOD1 fibrils in vitro (Fig.…”

“…This coexistence distinguishes the hSOD1 D90A mice from previous disease models where the variation of strains is typically observed between individuals (1,34,35,41). Even so, the hSOD1 D90A mice highlight the notion that strain variation influences pathology, as previously observed for prions (27,28), and in patients and models for synucleopathies (33), Alzheimer's disease (1,35,36), and tauopathies (34).…”

“…In several other protein-disease models, there is evidence for a positive correlation between aggregate "fragility" (i.e., how easily they break apart under mechanical stress and neuroinvasiveness/toxicity) (27)(28)(29)(30). A corresponding relationship between aggregate fragility and growth has also been predicted theoretically (4):…”

Isolation of Novel Synthetic Prion Strains by Amplification in Transgenic Mice Coexpressing Wild-Type and Anchorless Prion Proteins

“…The category 2 agent (e.g., the C413 agent) is characterized by low to intermediate levels of PK-resistant PrP on initial passage, higher specific infectivity, lower amyloidogenicity, and increased compatibility with wt PrP C , thereby allowing efficient propagation in mice expressing either anchorless or wt PrP C . The second category also templates PrP res conformers with lower stability that may correspond to agents with increased fitness (7,17,34). The relationship between fitness and stability is under debate for hamster scrapie strains (3).…”

Analysis of Conformational Stability of Abnormal Prion Protein Aggregates across the Spectrum of Creutzfeldt-Jakob Disease Prions

“…Similarly, sedimentation profiles and protease sensitivity have been used as indirect markers of PrP Sc structure and have shown a correlation with strain-specific transmission properties (22)(23)(24)(25)(26)(27). More recently, studies with rodent-adapted, cloned prion strains demonstrated that also the conformational stability of PrP Sc , measured indirectly either by inducing a progressive denaturation of the protein with the chaotropic salt guanidine hydrochloride (GdnHCl) or by exposing the protein to increasing temperatures in the presence of sodium dodecyl sulfate (SDS), may vary among different strains (28)(29)(30). Attempts have also been made to correlate PrP Sc conformational stability to strain-specific properties such as replication rates, although with conflicting, opposite results in murine and hamster models (28)(29)(30).…”