Efficient interspecies transmission of synthetic prions.

Alyssa J. Block,Ryan W. Walters,Ronald A. Shikiya,Jason C. Bartz,Thomas E. Eckland,Anthony E. Kincaid,Jiyan Ma,Surachai Supattapone

doi:10.1371/journal.ppat.1009765

Alyssa J. Block, Ryan W. Walters + Show 6 more

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https://doi.org/10.1371/journal.ppat.1009765

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Abstract

Prions are comprised solely of PrPSc, the misfolded self-propagating conformation of the cellular protein, PrPC. Synthetic prions are generated in vitro from minimal components and cause bona fide prion disease in animals. It is unknown, however, if synthetic prions can cross the species barrier following interspecies transmission. To investigate this, we inoculated Syrian hamsters with murine synthetic prions. We found that all the animals inoculated with murine synthetic prions developed prion disease characterized by a striking uniformity of clinical onset and signs of disease. Serial intraspecies transmission resulted in a rapid adaptation to hamsters. During the adaptation process, PrPSc electrophoretic migration, glycoform ratios, conformational stability and biological activity as measured by protein misfolding cyclic amplification remained constant. Interestingly, the strain that emerged shares a strikingly similar transmission history, incubation period, clinical course of disease, pathology and biochemical and biological features of PrPSc with 139H, a hamster adapted form of the murine strain 139A. Combined, these data suggest that murine synthetic prions are comprised of bona fide PrPSc with 139A-like strain properties that efficiently crosses the species barrier and rapidly adapts to hamsters resulting in the emergence of a single strain. The efficiency and specificity of interspecies transmission of murine synthetic prions to hamsters, with relevance to brain derived prions, could be a useful model for identification of structure function relationships between PrPSc and PrPC from different species.

Highlights

IntroductionPrions are comprised of PrPSc, the self-templating disease specific conformation of the cellular prion protein, PrPC [1,2,3,4,5,6]
Prion diseases are a group of inevitably fatal neurodegenerative disorders that affect a wide range of mammalian species including Sapiens
Prions have zoonotic potential as illustrated by the interspecies transmission of bovine spongiform encephalopathy to humans resulting in the emergence of a novel human prion disease

Summary

Introduction

Prions are comprised of PrPSc, the self-templating disease specific conformation of the cellular prion protein, PrPC [1,2,3,4,5,6]. Prion diseases are characterized by a long subclinical incubation period followed by a comparatively short clinical phase, spongiform degeneration, and accumulation of PrPSc in the central nervous system [7,8,9,10]. Transmission of prions to a new species can result in an extension of the incubation period and a reduction in attack rate compared to transmission in the original host [15]. Subsequent passages in the new host species can result in a shortening of the incubation period and stabilization of the disease phenotype [16,17,18,19,20]. Prediction of the zoonotic potential of emerging prion diseases, such as chronic wasting disease, or prion strains within a species (e.g., C-type and Htype bovine spongiform encephalopathy), requires direct empirical evidence [31, 32]

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