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

ABSTRACT: The 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.We 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.

SUBMITTER: Vrentas CE

PROVIDER: S-EPMC5738711 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Vrentas Catherine E CE Greenlee Justin J JJ Foster Gregory H GH West James J Jahnke Marianna M MM Schmidt Mark T MT Nicholson Eric M EM

BMC research notes 20171220 1

<h4>Objective</h4>The 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 i ...[more]

PMID: 29262866

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Project description:BackgroundAbnormal aggregation of proteins induces neuronal cell loss in neurodegenerative disorders such as Alzheimer's Disease, Creutzfeldt-Jakob Disease and Parkinson's Disease. Specific stimuli initialize conformational changes in physiological proteins, causing intra- or extracellular protein aggregation. We and other groups have identified naturally occurring autoantibodies (nAbs) as part of the human antibody pool that are able to prevent peptide fibrillation. These nAbs show a rescue effect following exposure of toxic aggregates on neurons, and they support microglial uptake of aggregated peptides.ObjectiveIdentification of a putative common epitope among the relevant proteins β-Amyloid, α-Synuclein and Prion Protein for the respective nAbs.Material and methodsBinding affinity between the aforementioned proteins and nAbs was tested by Dot Blot, ELISA and SPR-technology. Furthermore, the functionality of the protein-nAbs-complexes was studied in Thioflavin-T assays and microglial uptake experiments to study dependent inhibition of protein aggregation and enhancement of Fcγ mediated uptake by microglial cells.Resultsβ-Amyloid and Prion Protein fragment showed considerable binding affinity and functional efficacy for all applied nAbs. Thereby, no significant difference within the different nAbs was detected. In contrast, α-Synuclein was bound exclusively by nAbs-α-Synuclein, which was reproduced in all binding studies. Surprisingly, functional assays with α-Synuclein revealed no significant effect of nAbs in comparison to IVIg treatment. However, all applied nAbs as well as IVIg show a minimal functionality on the microglial uptake of α-Synuclein.ConclusionnAbs-Aβ, nAbs-PrP possibly display comparable affinity to the same structural epitope within Aβ and PrP106-126 A117V whereas the epitope recognized by nAbs-α-Syn is only present in α-Syn. The structural similarity of Aβ and PrP fragment promotes the outline for an efficient antibody for the treatment of several neurodegenerative disorders and extend the functional characteristics of the investigated nAbs.

Dataset Information

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

Publications

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

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