Epigenetic Dominance of Prion Conformers

PLoS Pathogens

Shawn Browning¹  Hae-Eun Kang¹  Sehun Kim¹  Jifeng Bian²  Nora Hunter²  Eri Saijo²  Kristi G. Bowling²  Glenn C. Telling³ 

[1] Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky, United States of America;Prion Research Center (PRC) and Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America;The Roslin Institute and the University of Edinburgh, Midlothian, United Kingdom, and Cellular and Molecular Biology (CMB) Program and Molecular and Cellular Integrated Neuroscience (MCIN) Program, Colorado State University, Fort Collins, Colorado, United States of America

关键词: Animal prion diseases;    Sheep;    Scrapie;    Mouse models;    Central nervous system;    Veterinary diseases;    Brain diseases;    Alleles;   

DOI  :  10.1371/journal.ppat.1003692

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Although they share certain biological properties with nucleic acid based infectious agents, prions, the causative agents of invariably fatal, transmissible neurodegenerative disorders such as bovine spongiform encephalopathy, sheep scrapie, and human Creutzfeldt Jakob disease, propagate by conformational templating of host encoded proteins. Once thought to be unique to these diseases, this mechanism is now recognized as a ubiquitous means of information transfer in biological systems, including other protein misfolding disorders such as those causing Alzheimer's and Parkinson's diseases. To address the poorly understood mechanism by which host prion protein (PrP) primary structures interact with distinct prion conformations to influence pathogenesis, we produced transgenic (Tg) mice expressing different sheep scrapie susceptibility alleles, varying only at a single amino acid at PrP residue 136. Tg mice expressing ovine PrP with alanine (A) at (OvPrP-A136) infected with SSBP/1 scrapie prions propagated a relatively stable (S) prion conformation, which accumulated as punctate aggregates in the brain, and produced prolonged incubation times. In contrast, Tg mice expressing OvPrP with valine (V) at 136 (OvPrP-V136) infected with the same prions developed disease rapidly, and the converted prion was comprised of an unstable (U), diffusely distributed conformer. Infected Tg mice co-expressing both alleles manifested properties consistent with the U conformer, suggesting a dominant effect resulting from exclusive conversion of OvPrP-V136 but not OvPrP-A136. Surprisingly, however, studies with monoclonal antibody (mAb) PRC5, which discriminates OvPrP-A136 from OvPrP-V136, revealed substantial conversion of OvPrP-A136. Moreover, the resulting OvPrP-A136 prion acquired the characteristics of the U conformer. These results, substantiated by in vitro analyses, indicated that co-expression of OvPrP-V136 altered the conversion potential of OvPrP-A136 from the S to the otherwise unfavorable U conformer. This epigenetic mechanism thus expands the range of selectable conformations that can be adopted by PrP, and therefore the variety of options for strain propagation.

【 授权许可】

CC BY