Explorer Epigenetic dominance of prion conformers

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 OvPrPA136 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. Citation: Saijo E, Kang H-E, Bian J, Bowling KG, Browning S, et al. (2013) Epigenetic Dominance of Prion Conformers. PLoS Pathog 9(10): e1003692. doi:10.1371/ journal.ppat. 1003692 Editor: David Westaway, University of Alberta, Canada Received February 27, 2013; Accepted August 25, 2013; Published October 31, 2013 Copyright: 2013 Saijo 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. Funding: This work was supported by NIH grants RO1 NS040334 (GCT), PO1 AI077774 (GCT), and by Defra UK for project SE1440 (NH and GCT, http://www.nih. gov; http://www.defra.gov.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: glenn.telling@colostate.edu ¤a Current address: Laboratory of Persistent Viral Diseases (LPVD), Rocky Mountain Laboratories, NIH/NIAID, Hamilton, Montana, United States of America. ¤b Current address: Rice University Center for Technology in Teaching and Learning, Houston, Texas, United States of America. ¤c Current address: Cytonics, Jupiter, Florida, United States of America.