Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection

Abstract

Background: Mechanism of prion adaptation and evolution has not been fully elucidated. Results: Distinct human prion particles co-exist and undergo competitive selection during replication. Conclusion: The process is governed by preferential replication of the least stable pathogenic conformers. Significance: The spectrum of conformers in wild human prion isolates enables adaptation and evolution by selection of the progressively less stable and faster replicating subset.

Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease

“…TgNN6h mice express human PrP-129M with the two N-linked glycosylation sites mutated to eliminate glycosylation (24), whereas TgWV mice express wild-type human PrP-129V (25). We observed that TgNN6h and TgWV mice were susceptible to sCJDMM2 or sCJDVV2 prion strains, respectively, after an intracerebral inoculation of 129 polymorphism-matched sCJD brain homogenates; this was confirmed by Western blotting (fig.…”

Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases

“…These findings provided the first experimental evidence for an evolutionary process within the Type 1+2 prion mixture, with selection that favors Type 1 conformers with the lowest stability. 34 The initial preferential amplification rate of Type 1 PrP Sc is not surprising, since there is typically a higher percentage of less stable protease sensitive oligomers in Type 1 PrP Sc , as found in our recent studies. This may explain why this rPrP Sc subtype represents ~70% of all sCJD cases.…”

“…27,32,33 Subsequent experiments with sedimentation velocity separation using high speed centrifugation in sucrose gradient revealed that sCJD prions exist in the continuum of particles composed of <20 to >600 PrP Sc molecules. 34 The fragments were present at different ratios, and indicate co-occurrence of markedly different PrP Sc conformers, often in the same anatomical structure in the same brain. These quantitative findings extended previous qualitative observations with diverse antibodies and western blot techniques.…”

“…31,49,51 To investigate the impact of the coexistent prion particle types on this process, we recently used a modified protein misfolding cyclic amplification (PMCA) 52 with homologous, as well as mutant, unglycosylated PrP C(N181, 197Q ) substrate carrying methionine in codon 129. 34 The serial PMCA of "pure" Type MM1 and mixed Type MM1+2 sCJD seeds underwent two distinct phases. In the first adaptation phase, the amplification was limited, and detectable only with CDI.…”

“…[55][56][57][58] Since we observed no direct interaction between different conformers of PrP Sc in our in vitro mixing experiments with "pure" MM1 and MM2 sCJD prions, we concluded that the most likely explanation is competition for PrP C substrate or auxiliary molecule; however, the exact molecular mechanism of this phenomenon remains to be fully elucidated. 34 Cumulatively, the distinct particle size, conformational stability, and amplification rate of these prion subtypes argue for the frequent coexistence of different sCJD prions in the same host (Fig. 1).…”