Species barriers for chronic wasting disease by in vitro conversion of prion protein

Subject: Species barriers for chronic wasting disease by in vitro conversion of prion protein
Date: November 3, 2007 at 10:57 am PST

Species barriers for chronic wasting disease by in vitro conversion of prion protein

Li Li a, Michael B. Coulthart b, Aru Balachandran c, Avi Chakrabartty d, Neil R. Cashman a,* a Brain Research Centre, Division of Neurology, Department of Medicine, University of British Columbia and Vancouver Coastal Health, UBC Hospital, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5 b Prion Diseases Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Man., Canada R3E 3R2 Q1 c National Reference Laboratory for Scrapie and CWD, Animal Diseases Research Institute, Canadian Food Inspection Agency, 3851 Fallowfield Road, Nepean, Ont., Canada K2H 8P9 d University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, Ont., Canada M5G 1L7 Received 6 October 2007

Abstract

Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy that can affect North American cervids (deer, elk, and moose). Using a novel in vitro conversion system based on incubation of prions with normal brain homogenates, we now report that PrPCWD of elk can readily induce the conversion of normal cervid PrP (PrPC) molecules to a protease-resistant form, but is less efficient in converting the PrPC of other species, such as human, bovine, hamster, and mouse. However, when substrate brain homogenates are partially denatured by acidic conditions (pH 3.5), PrPCWD-induced conversion can be greatly enhanced in all species. Our results dem- onstrate that PrPC from cervids (including moose) can be efficiently converted to a protease-resistant form by incubation with elk CWD prions, presumably due to sequence and structural similarities between these species. Moreover, partial denaturation of substrate PrPC can apparently overcome the structural barriers between more distant species.

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Although Syrian hamsters were initially deemed resistant to CWD [19], a recent publication demonstrates that CWD can be transmitted and adapted to hamster [20].

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Substrate denaturation and human health


We confirm with multiple species that acid/GdnHCl-
treated brain PrPC is a superior substrate for in vitro con-
version than untreated PrPC, possibly by overcoming con-
formational barriers in partial denaturation of substrate
PrPC. PrP conversion in scrapie-infected neuroblastoma
cells is believed to occur in endosomes, a low-pH and
reducing environment [26]. The non-ruminant stomach
possesses a low pH lumen, and PrPC is expressed in this
organ [27]. Such acidic (denaturing) organ or cellular
organellar environments might also promote CWD trans-
mission to non-cervid species, including humans.

Acknowledgments

This work was supported by the Canadian Institutes of
Health Research (Institute of Infection and Immunity, Safe
Food and Water program) and PrioNet Canada.


[20] G.J. Raymond, L.D. Raymond, K.D. Meade-White, A.G. Hughson,
C. Favara, D. Gardner, E.S. Williams, M.W. Miller, R.E. Race, B.
Caughey, Transmission and adaptation of chronic wasting disease to
hamsters and transgenic mice: evidence for strains, J. Virol. 81 (2007)
4305–4314.


http://jvi.asm.org/cgi/content/abstract/81/8/4305


2007 Elsevier Inc. All rights reserved.

Please cite this article in press as: L. Li et al., Species barriers for
chronic wasting disease by in vitro...,
Biochem. Biophys. Res. Commun. (2007), doi:10.1016/j.bbrc.2007.10.087

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