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

Abstract

ObjectiveThe most common hereditary prion disease is human Creutzfeldt-Jakob disease (CJD), associated with a mutation in the prion gene 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 limitations including inconsistencies in disease presentation, requirement for mixed species chimeric protein constructs, and the relatively short life span and time to disease onset in rodents. These factors limit research on the mechanism by which the mutation drives disease development. Therefore, our objective was to provide the first assessment of cattle carrying the homologous mutation, E211K, as a system for investigating longer-term disease mechanisms. The E211K substitution was associated with a case of bovine spongiform encephalopathy from 2006.ResultsWe assessed the molecular properties of bovine E211K prion protein, characterized the molecular genetics of a population of cattle E211K carriers (offspring of the original EK211 cow) in relation to findings in humans, and generated preliminary evidence that the impacts of copper-induced oxidative stress may be different in cattle as compared to observations in transgenic mouse models. The cattle E211K system provides the opportunity for future analysis of physiological changes over time.Electronic supplementary materialThe online version of this article (10.1186/s13104-017-3085-8) contains supplementary material, which is available to authorized users.

Thermodynamic characterization for the denatured state of bovine prion protein and the BSE Associated variant E211K

“…Lacking native state differences, denatured state differences or substantial differences in the thermodynamic parameters describing stability, the substitution of lysine for glutamic acid results in genetic prion disease through mechanisms not exclusively related to the folding and stability of PrP, with some functional aspect such as metal ion binding also influencing the misfolding process. Suggestions have been made that this may occur due to differences in the oxidative stress response [27] or levels of expression for the disease associated variant [28], data available to date does not support this [29] in cattle.…”

Can a Micronutrient Mixture Delay the Onset and Progression of Symptoms of Single-Point Mutation Diseases?

“…Individuals carrying mutations in these genes show an early onset of PD symptoms. fCJD fCJD is an autosomal dominant single-point mutation disease in which lysine is substituted with glutamic acid in the mutated prion protein (PrPc) (10). Misfolding of normal PrPc into PrPsc causes disease phenotype.…”