Transgenetic Studies of prion Disease in Cervids

Chronic wasting disease (CWD) of cervids is a disease belonging to a group of fatal transmissible neurodegenerative disorders caused by prions. The mechanism of prion replication is unique, the central event being the coercion of host encoded prion protein (PrPc) by the disease-associated isoform (PrPSc) to adopt to the infectivity-associated conformation. The origins and the mode of transmission of CWD remain unclear. It is also unknown whether there are different strains of CWD prions or whether CWD poses a risk to humans or to other species. Understanding the risk that CWD poses to humans is of paramount importance in light of evidence that a new variant of Creutzfldt-Jakob disease (CJD) in humans in the United Kingdom, known as vCJD, results from exposure to prions from cattle with bovine spongiform encephalopathy, or 'mad cow disease'. The major objectives of the proposed research are to develop a rapid and sensitive bioassay for CWD prions in which to study CWD pathogenesis and to address the potential for intermammalian transmission of CWD prions. Expression of foreign prion protein (PrP) genes in transgenic (Tg) mice has been an extremely effective means of studying human and other animal prion diseases. The investigators propose three Specific Aims: (l) To develop Tg mice expressing cervid PrP or chimeric mouse/cervid PrP that will be the first reliable bioassay for the rapid and sensitive detection of CWD prions; (2) To investigate the prevalence of CWD prion strains in captive and wild populations of mule deer, white tailed deer and Rocky Mountain elk and assess the effect of cervid PrP polymorphisms at codons 129 and 138 on CWD susceptibility; and, (3) To use Tg models of human and bovine prion diseases as a means of determining the risks that CWD prions pose to humans and livestock. The results of these studies will provide the first reliable assay for detecting infectious CWD prions and will provide crucial information about CWD prion species barriers and strains. The study of intermammalian species barriers in Tg mice will allow more accurate assessments of the risks posed to humans and livestock from exposure to CWD prions. More generally, these studies will further our understanding of the molecular mechanisms of prion pathogenesis that will ultimately result in rational approaches to therapies for human and animal prion diseases.