Genetic modulation of CWD prion propagation in cervid PrP Drosophila.
Genetic modulation of CWD prion propagation in cervid PrP Drosophila.
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DOI：
10.1042/bcj20230247
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发表时间：
2023-10-11
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
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慢性消耗性疾病是鹿、麋鹿、驼鹿和驯鹿等鹿科动物的一种致命的朊病毒疾病。这种情况下，北美鹿科动物的朊病毒感染性分泌和排泄导致环境污染，随后在自由放养和养殖的鹿科动物中进行有效的横向传播。鹿PrP的变异体存在，影响宿主对慢性消耗性疾病的易感性。旨在增加与慢性消耗性疾病抗性相关的PrP变体频率的鹿科动物育种计划可能会减少动物中这种疾病的负担，并降低人畜共患病的风险。该策略需要一个相对快速且经济上可行的模型系统来表征和支持选择朊病毒疾病修饰的鹿PrP变体。在这里，我们产生了cervid PrP转基因果蝇，以满足这一目的。我们已经产生了S138野生型cervid PrP转基因果蝇，或与慢性消耗性疾病抗性相关的N138变体。我们表明，鹿PrP果蝇在接触鹿朊病毒后会积累真正的朊病毒感染性。此外，当通过运动能力或生存加速丧失的表型评估或通过朊病毒接种活性积累的生化评估时，S138和N138 PrP飞系对来自北美或欧洲的鹿朊病毒分离物易感。然而，暴露于欧洲驯鹿朊病毒后，N138 PrP果蝇积累朊病毒播种活性的动力学比S138飞线慢。这些新的数据表明，朊病毒的敏感性特征的cervid PrP变体保持表达时，在果蝇，这突出了这种新的无脊椎动物的主机在建模慢性消耗性疾病。
Chronic wasting disease is a fatal prion condition of cervids such as deer, elk, moose and reindeer. Secretion and excretion of prion infectivity from North American cervids with this condition causes environmental contamination and subsequent efficient lateral transmission in free-ranging and farmed cervids. Variants of cervid PrP exist that affect host susceptibility to chronic wasting disease. Cervid breeding programmes aimed at increasing the frequency of PrP variants associated with resistance to chronic wasting disease may reduce the burden of this condition in animals and lower the risk of zoonotic disease. This strategy requires a relatively rapid and economically viable model system to characterise and support selection of prion disease-modifying cervid PrP variants. Here, we generated cervid PrP transgenic Drosophila to fulfil this purpose. We have generated Drosophila transgenic for S138 wild type cervid PrP, or the N138 variant associated with resistance to chronic wasting disease. We show that cervid PrP Drosophila accumulate bona fide prion infectivity after exposure to cervid prions. Furthermore, S138 and N138 PrP fly lines are susceptible to cervid prion isolates from either North America or Europe when assessed phenotypically by accelerated loss of locomotor ability or survival, or biochemically by accumulation of prion seeding activity. However, after exposure to European reindeer prions, N138 PrP Drosophila accumulated prion seeding activity with slower kinetics than the S138 fly line. These novel data show that prion susceptibility characteristics of cervid PrP variants are maintained when expressed in Drosophila, which highlights this novel invertebrate host in modelling chronic wasting disease.
DOI：
10.1093/brain/awy183
发表时间：
2018-09-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Thackray AM;Andréoletti O;Bujdoso R
通讯作者：
Bujdoso R
DOI：
10.1016/j.jbc.2021.100878
发表时间：
2021-08
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Thackray AM;Andréoletti O;Spiropoulos J;Bujdoso R
通讯作者：
Bujdoso R
影响因子：
3.5
作者：
Haley N;Donner R;Merrett K;Miller M;Senior K
通讯作者：
Senior K