Moore S Jo, Vrentas Catherine E, Hwang Soyoun, West Greenlee M Heather, Nicholson Eric M, Greenlee Justin J
USDA, Agricultural Research Service, National Animal Disease Center, Virus and Prion Research Unit, Ames, USA.
Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, USA.
BMC Vet Res. 2018 Mar 9;14(1):80. doi: 10.1186/s12917-018-1400-9.
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.
Elk with longer incubation periods accumulated relatively less PrP in the brain than elk with shorter incubation periods. PrP accumulation in LM132 and MM132 elk was primarily neuropil-associated while glial-associated immunoreactivity was prominent in LL132 elk. The fibril stability of PrP from MM132 and LM132 elk were similar to each other and less stable than that from LL132 elk. Real-time quaking induced conversion assays (RT-QuIC) revealed differences in the ability of PrP seed from elk of different genotypes to convert recombinant 132 M or 132 L substrate.
This study provides further evidence of the importance of PRNP genotype in the pathogenesis of CWD of elk. The longer incubation periods observed in LL132 elk are associated with PrP that is more stable and relatively less abundant at the time of clinical disease. The biochemical properties of PrP from MM132 and LM132 elk are similar to each other and different to PrP from LL132 elk. The shorter incubation periods in MM132 compared to LM132 elk may be the result of genotype-dependent differences in the efficiency of propagation of PrP moieties present in the inoculum. A better understanding of the mechanisms by which the polymorphisms at codon 132 in elk PRNP influence disease pathogenesis will help to improve control of CWD in captive and free-ranging elk populations.
落基山麋鹿（Cervus elaphus nelsoni）的朊病毒蛋白基因（PRNP）在密码子132处具有多态性，群体中存在亮氨酸（L132）和甲硫氨酸（M132）等位基因变体。在用慢性消耗病（CWD）病原体进行实验接种的麋鹿中，不同的潜伏期与PRNP基因型相关：LL132基因型的麋鹿存活时间最长，LM132基因型的麋鹿居中，MM132基因型的麋鹿最短。本研究的目的是调查不同朊病毒蛋白基因型的麋鹿潜伏期变化的潜在机制。对三种PRNP基因型的麋鹿幼崽（n = 2只MM132、n = 2只LM132、n = 4只LL132）口服接种来自临床感染CWD的麋鹿的脑匀浆。
潜伏期较长的麋鹿大脑中积累的PrP相对少于潜伏期较短的麋鹿。LM132和MM132基因型麋鹿中的PrP积累主要与神经毡相关，而在LL132基因型麋鹿中与胶质细胞相关的免疫反应性较为突出。MM132和LM132基因型麋鹿的PrP纤维稳定性彼此相似，且比LL132基因型麋鹿的PrP纤维稳定性更低。实时震颤诱导转化分析（RT-QuIC）显示，来自不同基因型麋鹿的PrP种子转化重组132M或132L底物的能力存在差异。
本研究进一步证明了PRNP基因型在麋鹿CWD发病机制中的重要性。在LL132基因型麋鹿中观察到的较长潜伏期与临床疾病发生时更稳定且相对含量较低的PrP有关。MM132和LM132基因型麋鹿的PrP生化特性彼此相似，与LL132基因型麋鹿的PrP不同。与LM132基因型麋鹿相比，MM132基因型麋鹿较短的潜伏期可能是接种物中存在的PrP部分传播效率的基因型依赖性差异的结果。更好地理解麋鹿PRNP密码子132处的多态性影响疾病发病机制的方式，将有助于改善对圈养和野生麋鹿群体中CWD的控制。
