Pathologic and biochemical characterization of PrPSc from elk with PRNP polymorphisms at codon 132 after experimental infection with the chronic wasting disease agent

Authors: MOORE, SARAH - Orise Fellow; Vrentas, Catherine; Hwang, Soyoun; WEST GREENLEE, M - Iowa State University; Nicholson, Eric; Greenlee, Justin

Submitted to: BMC Veterinary Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/27/2018
Publication Date: 3/9/2018
Citation: Moore, S.J., Vrentas, C.E., Hwang, S., West Greenlee, M.H., Nicholson, E.M., Greenlee, J.J. 2018. Pathologic and biochemical characterization of PrPSc from elk with PRNP polymorphisms at codon 132 after experimental infection with the chronic wasting disease agent. BMC Veterinary Research. 14(1):80. https://doi.org/10.1186/s12917-018-1400-9.
DOI: https://doi.org/10.1186/s12917-018-1400-9

Interpretive Summary: Chronic wasting disease (CWD) is a fatal disease of deer and elk that causes damaging changes in the brain. The infectious agent is an abnormal protein called a prion that has misfolded from its normal state. Whether or not an elk will get CWD is affected by their genetics. This study evaluated pathologic features and properties of abnormal prion protein from elk of 3 different genotypes that were infected with CWD. The genetic differences tested were at codon 132 in the elk prion protein, which is homologous to the human codon 129 that is associated with susceptibility to human prion diseases. Our data indicates that there are differences in incubation periods, patterns of abnormal prion accumulation in the brain, and fibril stability features in these different genotypes of elk. While no genotype is resistant to CWD, elk expressing the amino acid leucine at codon 132 of the prion protein do have greatly prolonged incubation periods. These long incubation periods are associated with more stable prion fibrils. These findings suggest that genetic selection for the L132 allele has the potential to reduce (but probably not eliminate) the impact of CWD in captive and free-ranging elk populations. This information is useful to wildlife managers and captive wildlife owners that are selectively breeding animals and could impact future regulations for the control of CWD in the United States

Technical Abstract: The Rocky Mountain elk (Cervus elaphus nelsoni) prion protein gene (PRNP) is polymorphic at codon 132, with leucine (L132) and methionine (M132) allelic variants present in the population. In elk experimentally inoculated with the chronic wasting disease (CWD) agent, different incubation periods are associated with PRNP genotype: LL132 elk survive the longest, LM132 elk are intermediate, and MM132 elk the shortest. The purpose of this study was to investigate potential mechanisms underlying variations in incubation period in elk of different prion protein genotypes. Elk calves of three PRNP genotypes (n=2 MM132, n=2 LM132, n=4 LL132) were orally inoculated with brain homogenate from elk clinically-affected with CWD. The incubation period in inoculated elk was found to be proportional to the relative amount of PrPSc in the brain. The fibril stability of PrPSc from MM132 and LM132 elk were similar to each other and less stable than that from LL132 elk. Real-time quaking induced conversion assays seeded with LL132 had a shorter lag phase than reaction mixtures seeded with LM132 and MM132. The longer incubation periods observed in LL132 elk are associated with PrPSc that is relatively less abundant at the time of clinical disease, more stable, and has a higher amyloid formation rate.