Effects of a naturally occurring amino acid substitution in bovine PrP: a model for inherited prion disease in a natural host species

Authors: Vrentas, Catherine; Greenlee, Justin; Foster, Gregory; WEST, JAMES - Iowa State University; JAHNKE, MARIANNA - Iowa State University; Schmidt, Mark; Nicholson, Eric

Submitted to: BMC Research Notes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/13/2017
Publication Date: 12/20/2017
Citation: Vrentas, C.E., Greenlee, J.J., Foster, G.H., West, J., Jahnke, M.M., Schmidt, M.T., Nicholson, E.M. 2017. Effects of a naturally occurring amino acid substitution in bovine PrP: a model for inherited prion disease in a natural host species. BMC Research Notes. 10:759. https://doi.org/10.1186/s13104-017-3085-8.

Interpretive Summary: Prion diseases in humans, including the fatal and neurodegenerative Creutzfeldt-Jakob disease (CJD), are associated with the misfolding of the prion protein into an aberrant form in the nervous system. Disease in humans can arise from consumption of contaminated food, medical transmission, spontaneous accumulation of misfolded prion protein, or inheritance of a mutation in the gene which encodes the prion protein. The most common inherited mutation in the prion gene is known as E200K, which denotes the corresponding change in the protein sequence; no therapies are currently available to treat individuals with this genetic mutation. Until recently, no examples of inherited, disease-causing mutations were known in livestock. In 2006, a case of bovine spongiform encephalopathy (BSE) was identified in an older beef cow which carried a change in its prion gene corresponding to the human E200K gene (E211K in cattle). While previous studies did not identify this genetic mutation in other cattle, meaning that it is not a threat to the food supply, E211K cattle can serve as an experimental model to increase our understanding of the link between this genetic change and disease pathology in humans. Their relatively long life span and the fact that cattle are a natural host for prion diseases, with a relatively low transmission barrier to humans, make cattle a superior model system to mouse models in certain respects. Here, we provide a preliminary report of the properties of a small experimentally-bred herd of cattle bearing this genetic mutation, including a characterization of the molecular genetics of these cattle and a molecular validation of these cattle as a model system. We utilize the cattle system to investigate the previous hypothesis that the E200K/E211K mutation causes oxidative stress that exacerbates disease. Finally, we delineate a series of ongoing experiments which will be useful in understanding the progression of inherited prion disease in the future.

Technical Abstract: The most common hereditary prion disease is human Creutzfeldt-Jakob disease (CJD) associated with a mutation in the prion gene (PRNP) resulting in a glutamic acid to lysine substitution at position 200 (E200K) in the prion protein. Models of E200K CJD in transgenic mice have proven interesting but have significant limitations including inconsistencies with regard to disease presentation, use of mixed species chimeric protein constructs, and the relatively short life span and time to disease onset in these animals. These factors limit the opportunity to effectively study the mechanism by which the mutation drives disease development. Here, we present the first model of E200K disease in a natural host: cattle carrying the homologous mutation, E211K. This amino acid substitution was associated with a case of bovine spongiform encephalopathy. We assess bovine prion protein as a model on the molecular level, characterized the molecular genetics of the cattle E211K carriers in relation to findings in humans, and provide preliminary evidence that the impacts of copper-induced oxidative stress may be different in cattle as compared to observations in transgenic mouse models utilizing chimeric sequences.