Alterations in prion mutant spectra precede strain breakdown in animals

Authors: BLOCK, ALYSSA - Creighton University; Bian, Jifeng; SHIKIYA, RONALD - Creighton University; BARTZ, JASON - Creighton University

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 3/31/2024
Publication Date: N/A
Citation: N/A

Interpretive Summary:

Technical Abstract: Objectives Prions are composed of PrPSc, the disease specific conformation of the host encoded prion protein. Treatment of rodents with anti-prion drugs results in the emergence of drug-resistant prion strains, suggesting prions are comprised of a dominant strain and substrains. While considerable experimental evidence supports this hypothesis, direct observation of substrains has not been observed. The objective of this study was to directly investigate if prion strains contain substrain diversity. Methods We investigated the presence of substrain diversity in a biologically stable hamster-adapted prion strain, DY TME and a biologically unstable hamster-adapted prion strain 139H that, following serial passage at high titer, can breakdown into a strain with a shorter incubation period. Both strains were probed for substrains by selectively reducing the abundance of the dominant strain PrPSc using either extended digestion with proteinase K or with chaotropic treatment or susceptibility to RK13 cell infection. The remaining PrPSc was subjected to protein misfolding cyclic amplification to probe for substrains. Results Selective reduction of DY or 139H PrPSc using a combination of biochemical methods resulted in the emergence of strains with properties that differed from DY or 139H and were consistent with the selection criteria. Substrains identified in 139H-infected brains were similar to the strains that emerged in animals following strain breakdown. Conclusions The substrain selection methods occurred outside of prion formation, providing direct evidence for the preexistence of substrains. Furthermore, we hypothesize that substrains are a common feature of prions as they were identified in a stable, biologically-cloned prion strain. The identification of preexisting substrains may contribute to the ability of prions to rapidly adapt to new replication environments such as transmission to a new species or replication in the presence of anti-prion drugs.