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Title: Elk with a long incubation prion disease phenotype have a unique PrP-d profile

item O'Rourke, Katherine
item Zhuang, Dongyue
item Greenlee, Justin
item Hamir, Amirali

Submitted to: NeuroReport
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/4/2007
Publication Date: 12/3/2007
Citation: O'Rourke, K.I., Spraker, T.R., Zhuang, D., Greenlee, J.J., Gidlewski, T.E., Hamir, A.N. 2007. Elk with a long incubation prion disease phenotype have a unique PrP-d profile. NeuroReport. 18(18):1935-1938.

Interpretive Summary: Chronic wasting disease is a fatal disease of deer and elk. Infected animals are clinically normal for prolonged periods, eventually developing a degenerative disorder of the brain. The period of time during which infected elk are clinically normal but capable of transmitting disease to herdmates is unknown. We have previously demonstrated that the gene for the normal prion protein affects the susceptibility of infected elk and that small changes in this gene are associated with a lengthening of the preclinical period. In this study, we examined experimentally infected elk of a relatively rare genetic background and determined that this genotype is associated with a preclinical period nearly triple that observed in elk of the most common genotype. The mechanism for this prolonged incubation period is not known. Biochemical analysis of the abnormal prion protein demonstrated differences in the folding pattern of these proteins in the brains of elk of the long incubation genotype in comparison to the short or moderate incubation period elk. A better understanding of the differences in protein processing in elk of different prion genotypes should be useful in developing methods for identifying and controlling the disease in farmed elk.

Technical Abstract: Chronic wasting disease is a transmissible spongiform encephalopathy of deer and elk in North America. All diseases in this family are characterized by long preclinical incubation periods following by a relatively short clinical course. Endpoint disease is characterized by extensive deposits of aggregates of the abnormal prion protein in the central nervous system, associated with neuronal loss. The abnormal prion protein is a relatively protease resistant isoform of the normal cellular protein, with major and minor proteinase K cleavage sites apparently associated with variation in posttranslational folding patterns. The disease phenotype of chronic wasting disease in Rocky Mountain elk includes differences in relative susceptibility to field challenge and in incubation time following experimental challenge. Incubation time is associated with polymorphisms in the gene encoding the prion protein, with homozygosity for leucine at codon 132 resulting in a prolonged and variable incubation period. In this study, we examined the differences in proteinase K cleavage site in samples from elk of three major prion genotypes following experimental challenge. Samples from elk with short and moderate incubation times had similar biochemical profiles. Samples from elk with the long incubation phenotype were significantly different in the size of the protease resistant core, indicating that the abnormal protein is folded in a novel pattern in elk of this genotype. No difference was noted in the peripheral distribution of the abnormal protein, suggesting that elk of this genotype may be long term carriers of CWD, shedding the infectious agent into the environment for long periods.