Evidence for preexisting prion substrain diversity in a biologically cloned prion strain.

Autor: Gunnels T; Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America., Shikiya RA; Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America., York TC; Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America., Block AJ; Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America., Bartz JC; Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2023 Sep 05; Vol. 19 (9), pp. e1011632. Date of Electronic Publication: 2023 Sep 05 (Print Publication: 2023).
DOI: 10.1371/journal.ppat.1011632
Abstrakt: Prion diseases are a group of inevitably fatal neurodegenerative disorders affecting numerous mammalian species, including Sapiens. Prions are composed of PrPSc, the disease specific conformation of the host encoded prion protein. Prion strains are operationally defined as a heritable phenotype of disease under controlled transmission conditions. Treatment of rodents with anti-prion drugs results in the emergence of drug-resistant prion strains and suggest that prion strains are comprised of a dominant strain and substrains. While much experimental evidence is consistent with this hypothesis, direct observation of substrains has not been observed. Here we show that replication of the dominant strain is required for suppression of a substrain. Based on this observation we reasoned that selective reduction of the dominant strain may allow for emergence of substrains. Using a combination of biochemical methods to selectively reduce drowsy (DY) PrPSc from biologically-cloned DY transmissible mink encephalopathy (TME)-infected brain resulted in the emergence of strains with different properties than DY TME. The selection methods did not occur during prion formation, suggesting the substrains identified preexisted in the DY TME-infected brain. We show that DY TME is biologically stable, even under conditions of serial passage at high titer that can lead to strain breakdown. Substrains therefore can exist under conditions where the dominant strain does not allow for substrain emergence suggesting that substrains are a common feature of prions. This observation has mechanistic implications for prion strain evolution, drug resistance and interspecies transmission.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Gunnels et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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