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.





snip...





Although Syrian hamsters were initially deemed resistant to CWD [19], a

recent publication demonstrates that CWD can be transmitted

and adapted to hamster [20].





snip...





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



http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WBK-4R04PFW-3&_user=1





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