Prion potentiation after life-long dormancy in mice devoid of PrP.
Prion potentiation after life-long dormancy in mice devoid of PrP.
复制标题
在没有PRP的小鼠中终生休眠后的prion增强。
DOI：
10.1093/braincomms/fcab092
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发表时间：
2021
影响因子：
4.8
通讯作者：
Béringue V
中科院分区：
文献类型：
--
作者：
Martin D;Reine F;Herzog L;Igel-Egalon A;Aron N;Michel C;Moudjou M;Fichet G;Quadrio I;Perret-Liaudet A;Andréoletti O;Rezaei H;Béringue V
朊病毒是嗜神经病原体，由宿主编码的朊病毒蛋白 PrPC 的错误折叠组件组成，通过自催化播种聚合过程招募和转化进一步的 PrPC 进行复制。虽然长期以来研究表明，适应小鼠的朊病毒不能在 PrPC 无效的转基因 PrP0/0 小鼠中复制并被快速清除，但这些实验尚未使用其他朊病毒进行，包括来自自然资源的朊病毒，以及检测朊病毒生物活性的更灵敏方法。使用表达人 PrP 的转基因小鼠来生物测定朊病毒感染性，并使用 RT-QuIC 无细胞测定来测量朊病毒播种活性，我们报告说，导致人类散发性克雅氏病 (MM1-sCJD) 最常见形式的朊病毒可以在脑内接种的 PrP0/0 小鼠的大脑中无限期地持续存在。虽然 RT-QuIC 在受攻击的 PrP0/0 小鼠大脑中测量到低水平的接种活性，但生物指示剂人源化小鼠的死亡率很高，表明持续感染性水平相对较高。值得注意的是，与以低剂量（包括限制剂量）直接接种的 MM1-sCJD 朊病毒相比，这些人源化小鼠的死亡动力学延迟。然而，在 PrP0/0 小鼠初次传代和随后回传的人源化小鼠中确实发生的疾病具有 MM1-sCJD 朊病毒的神经病理学和分子特征，表明在 PrP0/0 大脑的终身休眠期间没有明显的菌株进化。因此，MM1-sCJD 朊病毒可以在 PrP0/0 大脑中终生存在，并在逆向传播至易感宿主时具有潜在的疾病增强作用。这些发现强调了朊病毒在非复制环境中持续存在和恢复活力的能力，询问了工作中的朊病毒组装类型，并警惕了降低 PrP 治疗策略导致朊病毒无限期持续存在的风险。简短摘要 Martin 等人。报告称，在缺乏内源性朊病毒蛋白基因的小鼠大脑中，散发性克雅氏病朊病毒终生持续存在，并且在逆传至人源化小鼠时疾病增强（没有菌株进化）。这些发现强调了通过降低朊病毒蛋白的治疗策略导致朊病毒无限期持续存在的风险。
Prions are neurotropic pathogens composed of misfolded assemblies of the host-encoded prion protein PrPC which replicate by recruitment and conversion of further PrPC by an autocatalytic seeding polymerization process. While it has long been shown that mouse-adapted prions cannot replicate and are rapidly cleared in transgenic PrP0/0 mice invalidated for PrPC, these experiments have not been done with other prions, including from natural resources, and more sensitive methods to detect prion biological activity. Using transgenic mice expressing human PrP to bioassay prion infectivity and RT-QuIC cell-free assay to measure prion seeding activity, we report that prions responsible for the most prevalent form of sporadic Creutzfeldt–Jakob disease in human (MM1-sCJD) can persist indefinitely in the brain of intra-cerebrally inoculated PrP0/0 mice. While low levels of seeding activity were measured by RT-QuIC in the brain of the challenged PrP0/0 mice, the bio-indicator humanized mice succumbed at a high attack rate, suggesting relatively high levels of persistent infectivity. Remarkably, these humanized mice succumbed with delayed kinetics as compared to MM1-sCJD prions directly inoculated at low doses, including the limiting one. Yet, the disease that did occur in the humanized mice on primary and subsequent back-passage from PrP0/0 mice shared the neuropathological and molecular characteristics of MM1-sCJD prions, suggesting no apparent strain evolution during lifelong dormancy in PrP0/0 brain. Thus, MM1-sCJD prions can persist for the entire life in PrP0/0 brain with potential disease potentiation on retrotransmission to susceptible hosts. These findings highlight the capacity of prions to persist and rejuvenate in non-replicative environments, interrogate on the type of prion assemblies at work and alert on the risk of indefinite prion persistence with PrP-lowering therapeutic strategies. Abbreviated summary Martin et al. report lifelong persistence of sporadic Creutzfeldt–Jakob disease prions in the brain of mice lacking the endogenous prion protein gene and disease potentiation—without strain evolution—on retrotransmission to humanized mice. These findings highlight the risk of indefinite prion persistence with therapeutic strategies lowering the prion protein.
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影响因子：
4.8
作者：
Beringue, V;Vilette, D;Hawke, S
通讯作者：
Hawke, S
影响因子：
6.7
作者：
Burke, Cassandra M.;Walsh, Daniel J.;Supattapone, Surachai
通讯作者：
Supattapone, Surachai
影响因子：
0.8
作者：
FRASER, H;DICKINSON, AG
通讯作者：
DICKINSON, AG
影响因子：
7.2
作者：
Giles, Kurt;Woerman, Amanda L.;Prusiner, Stanley B.
通讯作者：
Prusiner, Stanley B.
影响因子：
64.8
作者：
Collinge, J;Sidle, KCL;Hill, AF
通讯作者：
Hill, AF