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Transmissible spongiform encephalopathies (TSEs) are an unusual class of fatal neurological diseases that include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE, also known as mad cow disease), transmissible mink encephalopathy, feline spongiform encephalopathy and CWD in deer and elk. The human diseases include Kuru maintained by ritualistic cannibalism, CJD that has sporadic, acquired and familial manifestations and two familial forms, Gerstmann-Straussler-Scheinker syndrome (GSS) and fatal familial insomnia. All TSEs have been experimentally transmitted to a number of species from non-human primates to rodents. Each of these diseases has its unique set of characteristics including range of species that can be infected. These characteristics differ between species and there are varying degrees of host restriction.
Chronic Wasting Disease: CWD is an emerging TSE in wild deer and elk in the U.S. and Canada. Since the first case of CWD was identified in a Colorado research facility in 1967 (Williams and Young, 1980), CWD has been identified in captive cervid populations in Wyoming, Wisconsin, Saskatchewan, South Dakota, Oklahoma, Nebraska, Montana, Minnesota and Alberta. In the free-ranging cervid population, CWD has been found in Wyoming, Wisconsin, Utah, South Dakota, Saskatchewan, New Mexico, Nebraska, Illinois, and Colorado. The detection of CWD in free-ranging and captive cervids from these ranges may be due in part to increased surveillance, but epidemiological data from expanding affected regions suggest that lateral transmission is the primary mode of disease spread (Miller et al., 2000). While scrapie in sheep transmits laterally, CWD is the first identified laterally transmitting TSE of free-ranging animals. In Wisconsin, the disease was identified in the southeastern portion of the state. Initially, the Wisconsin Department of Natural Resources established a 361-square-mile disease eradication zone. This zone has expanded to maintain a 4-mile buffer around all known CWD-positive animals. To date, 250 deer have tested positive in Wisconsin.
Prion Protein Gene & Genetic Susceptibility: It has been established for decades that genetic factors affect TSE infections. Traditional genetic studies combined with infectivity assays identified a gene whose expression influenced the incubation period of prion diseases. In mice, this gene was referred to as the scrapie incubation gene (Sinc) and, in sheep, as the scrapie incubation period gene (Sip). The identification of the prion protein gene (Prnp) and the subsequent sequencing of the gene in mice with differing Sinc alleles (Westaway et al., 1987) and sheep with differing Sip alleles determined that Prnp was the scrapie incubation allele. Further evidence supporting the role of the PrP genotype on TSE infections includes the susceptibility of humans homozygous for methionine at amino acid 129 to variant CJD. Human familial TSEs (familial CJD and GSS syndrome) are genetic disorders caused by mutations in the human Prnp. The requirement of PrPC for successful TSE infection has been conclusively demonstrated by Prnp ablation experiments in mice (Bueler et al., 1993). In those experiments, removal of Prnp followed by experimental infection of mouse-adapted TSE agent results in no infection occurring. Inserting a PrP transgene into these null mice results in infection by the appropriate TSE agent.
Deer and Elk Prion Protein Gene: PrP genes from elk, mule deer and white-tailed deer have been sequenced. Three allelic variants have been identified in white-tailed deer (Raymond et al., 2000) with the genetic variability occurring at amino acid residues 96 and 138. Since the frequency of these alleles in the wild deer population is not known, a goal of this project is to obtain a complete picture of PrP allelic variability and frequency in wild deer populations. Comparison of the PrP allelic frequency between infected and uninfected deer will indicate whether deer with specific PrP alleles differ in their susceptibility to CWD. Although the relationship between elk PrP genotype and CWD has been previously described (O’Rourke et al., 1999), there has not been a thorough analysis of the white-tailed deer PrP genotype in wild populations. In Wisconsin, the availability of a large number of animals as well as the large number of predicted positive animals will facilitate a complete analysis of the relationship between white-tailed deer PrP sequence and susceptibility to infection. We have sequenced the entire PrP coding region from both uninfected and CWD-positive deer.
The stated objectives for this work were: The goals of this proposal are to better understand the role of white-tailed deer prion protein (PrP) gene (Prnp) heterogeneity in susceptibility to chronic wasting disease (CWD) and to elucidate the role of PrPC in lateral transmission of this disease.
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