Prion strain mutation determined by prion protein conformational compatibility and primary structure.

Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky Medical Center, Lexington, KY 40536, USA.
Science (Impact Factor: 31.48). 05/2010; 328(5982):1154-8. DOI: 10.1126/science.1187107
Source: PubMed

ABSTRACT Prions are infectious proteins composed of the abnormal disease-causing isoform PrPSc, which induces conformational conversion of the host-encoded normal cellular prion protein PrPC to additional PrPSc. The mechanism underlying prion strain mutation in the absence of nucleic acids remains unresolved. Additionally, the frequency of strains causing chronic wasting disease (CWD), a burgeoning prion epidemic of cervids, is unknown. Using susceptible transgenic mice, we identified two prevalent CWD strains with divergent biological properties but composed of PrPSc with indistinguishable biochemical characteristics. Although CWD transmissions indicated stable, independent strain propagation by elk PrPC, strain coexistence in the brains of deer and transgenic mice demonstrated unstable strain propagation by deer PrPC. The primary structures of deer and elk prion proteins differ at residue 226, which, in concert with PrPSc conformational compatibility, determines prion strain mutation in these cervids.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prion disease is a unique category of illness, affecting both animals and humans, in which the underlying pathogenesis is related to a conformational change of a normal, self-protein called PrP(C) (C for cellular) to a pathological and infectious conformer known as PrP(Sc) (Sc for scrapie). Bovine spongiform encephalopathy (BSE), a prion disease believed to have arisen from feeding cattle with prion contaminated meat and bone meal products, crossed the species barrier to infect humans. Chronic wasting disease (CWD) infects large numbers of deer and elk, with the potential to infect humans. Currently no prionosis has an effective treatment. Previously, we have demonstrated we could prevent transmission of prions in a proportion of susceptible mice with a mucosal vaccine. In the current study, white-tailed deer were orally inoculated with attenuated Salmonella expressing PrP, while control deer were orally inoculated with vehicle attenuated Salmonella. Once a mucosal response was established, the vaccinated animals were boosted orally and locally by application of polymerized recombinant PrP onto the tonsils and rectal mucosa. The vaccinated and control animals were then challenged orally with CWD-infected brain homogenate. Three years post CWD oral challenge all control deer developed clinical CWD (median survival 602 days), while among the vaccinated there was a significant prolongation of the incubation period (median survival 909 days; p=0.012 by Weibull regression analysis) and one deer has remained CWD free both clinically and by RAMALT and tonsil biopsies. This negative vaccinate has the highest titers of IgA in saliva and systemic IgG against PrP. Western blots showed that immunoglobulins from this vaccinate react to PrP(CWD). We document the first partially successful vaccination for a prion disease in a species naturally at risk. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Vaccine 12/2014; 33(5). DOI:10.1016/j.vaccine.2014.11.035 · 3.49 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Transmissible spongiform encephalopaties (TSEs) are fatal neurodegenerative diseases characterized by the aggregation and accumulation of the misfolded prion protein in the brain. Other proteins such as β-amyloid, tau or Serum Amyloid-A (SAA) seem to share with prions some aspects of their pathogenic mechanism; causing a variety of so called prion-like diseases in humans and/or animals such as Alzheimer's, Parkinson's, Huntington's, Type II diabetes mellitus or amyloidosis. The question remains whether these misfolding proteins have the ability to self-propagate and transmit in a similar manner to prions. In this review, we describe the prion and prion-like diseases affecting animals as well as the recent findings suggesting the prion-like transmissibility of certain non-prion proteins. Copyright © 2014. Published by Elsevier B.V.
    Virus Research 11/2014; DOI:10.1016/j.virusres.2014.11.026 · 2.83 Impact Factor

Full-text (2 Sources)

Available from
May 17, 2014