Cervid Prion Protein Polymorphisms: Role in Chronic Wasting Disease Pathogenesis

Abstract

Chronic wasting disease (CWD) is a prion disease found in both free-ranging and farmed cervids. Susceptibility of these animals to CWD is governed by various exogenous and endogenous factors. Past studies have demonstrated that polymorphisms within the prion protein (PrP) sequence itself affect an animal's susceptibility to CWD. PrP polymorphisms can modulate CWD pathogenesis in two ways: the ability of the endogenous prion protein (PrP^C) to convert into infectious prions (PrP^Sc) or it can give rise to novel prion strains. In vivo studies in susceptible cervids, complemented by studies in transgenic mice expressing the corresponding cervid PrP sequence, show that each polymorphism has distinct effects on both PrP^C and PrP^Sc. It is not entirely clear how these polymorphisms are responsible for these effects, but in vitro studies suggest they play a role in modifying PrP epitopes crucial for PrP^C to PrP^Sc conversion and determining PrP^C stability. PrP polymorphisms are unique to one or two cervid species and most confer a certain degree of reduced susceptibility to CWD. However, to date, there are no reports of polymorphic cervid PrP alleles providing absolute resistance to CWD. Studies on polymorphisms have focused on those found in CWD-endemic areas, with the hope that understanding the role of an animal's genetics in CWD can help to predict, contain, or prevent transmission of CWD.

Keywords: cervid; chronic wasting disease; pathogenesis; polymorphism; prion protein; strain.

Figure 1

Chronic wasting disease (CWD) distribution in North America. Courtesy of the U.S. Geological Survey National Wildlife Health Center.

Figure 2

Chronic wasting disease (CWD) distribution in Scandinavia, based on Mysterud et al., 2020 [35]. Numbers in circles represent the number of CWD-positive animals.

Figure 3

Cervid prion protein sequence alignment showing conserved homology between species. Protein alignment was performed in Geneious v10.2.6 (https://www.geneious.com) (accessed on 15 December 2020) using the ClustalW algorithm. Amino acid numbering is based on the consensus sequence. Amino acid variants were added manually to each sequence and are shown in white boxes. NCBI accession numbers used in this alignment: (1) QAU19527.1, (2) ABW79881.1, (3) QAU19537.1, (4) AAO91945.1, (5) QKI87491.1, (6) AAT77253.1, (7) QHZ32187.1, (8) AGU92564.1, (9) ABA08026.1, (10) BAI50003.1, (11) BCK59655.1, (12) CAJ18553.1. β1, β2: first, second beta-strand; α1, α2, α3: first, second and third alpha-helix (based on mouse PrP numbering [136]). Refer to Table 1 for cervid species names in sequences 1–8. Non-cervid species names for sequences 9–12: O. = Ovis, B. = Bos, H. = Homo and M. = Mus.