Prion protein amino acid determinants of differential susceptibility and molecular feature of prion strains in mice and voles.
Prion protein amino acid determinants of differential susceptibility and molecular feature of prion strains in mice and voles.
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DOI：
10.1371/journal.ppat.1000113
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发表时间：
2008-07-25
期刊：
影响因子：
6.7
通讯作者：
Lipp HP
中科院分区：
文献类型：
--
作者：
Agrimi U;Nonno R;Dell'Omo G;Di Bari MA;Conte M;Chiappini B;Esposito E;Di Guardo G;Windl O;Vaccari G;Lipp HP
银行田鼠是一种啮齿动物，对来自人类和各种动物物种的不同朊病毒株易感。我们分析了不同的朊病毒在一个面板的7个啮齿动物物种，表现出不同程度的系统发育亲和力和特定的朊病毒蛋白（PrP）序列的分歧，以调查的基础上，田鼠易感性相比，其他啮齿动物模型的传输功能。首先，我们发现了不同的敏感性银行和外地田鼠相比，C57 B1/6和木材小鼠。田鼠表现出对羊瘙痒病的高敏感性，但对牛海绵状脑病有抵抗力，而C57 Bl/6和木鼠表现出相反的特征。感染小鼠适应性羊瘙痒症139 A是更快的田鼠比C57 Bl/6和木材小鼠。此外，在田鼠中观察到糖谱变化，其在回传至小鼠后恢复。适应新物种后，所有菌株在田鼠中的复制速度都比在小鼠中快得多。PrP序列比较表明，传输模式和154和169位氨基酸（小鼠中的Y和S，田鼠中的N和N）之间的相关性。当研究另外三种啮齿类动物（沙鼠、棘鼠和奥尔德菲尔德鼠）与羊瘙痒症和139 A的关系时，这种相关性得到了证实。选择这些啮齿动物是因为奥尔德菲尔德小鼠确实有154 N和169 N取代，而沙鼠和多刺小鼠没有。我们的结果表明，PrP残基154和169决定了啮齿动物中朊病毒株的易感性、分子表型和复制率。这可能对评估朊病毒株的宿主范围和分子可追溯性以及开发改进的朊病毒疾病动物模型具有意义。朊病毒是一种非传统的传染性病原体，可导致动物和人类致命的神经退行性疾病。一种病理形式的细胞朊病毒蛋白（PrPC），命名为PrPSc，似乎是朊病毒的主要或唯一组分。这些病原体通过诱导宿主PrPC转化为PrPSc而传播，PrPSc在受影响个体的大脑中积累。不同的因素被认为是调制这样的事件，这解释了在种间实验接种下观察到的可变传输效率。这些因素仍然是相当未知的，虽然有证据表明，感染性接种物的PrPSc和宿主的PrPC之间的某种结构相容性在使传播或多或少有效方面发挥作用。我们研究了朊病毒对不同啮齿动物的传播，发现朊病毒蛋白中的特定氨基酸取代（Y154 N和S169 N）是朊病毒易感性的主要决定因素。特别是，我们表明，这些特定的变化i）指导朊病毒在不同物种之间的传播速率，其方式取决于朊病毒菌株，ii）影响朊病毒的分子特征，iii）影响其复制效率。
The bank vole is a rodent susceptible to different prion strains from humans and various animal species. We analyzed the transmission features of different prions in a panel of seven rodent species which showed various degrees of phylogenetic affinity and specific prion protein (PrP) sequence divergences in order to investigate the basis of vole susceptibility in comparison to other rodent models. At first, we found a differential susceptibility of bank and field voles compared to C57Bl/6 and wood mice. Voles showed high susceptibility to sheep scrapie but were resistant to bovine spongiform encephalopathy, whereas C57Bl/6 and wood mice displayed opposite features. Infection with mouse-adapted scrapie 139A was faster in voles than in C57Bl/6 and wood mice. Moreover, a glycoprofile change was observed in voles, which was reverted upon back passage to mice. All strains replicated much faster in voles than in mice after adapting to the new species. PrP sequence comparison indicated a correlation between the transmission patterns and amino acids at positions 154 and 169 (Y and S in mice, N and N in voles). This correlation was confirmed when inoculating three additional rodent species: gerbils, spiny mice and oldfield mice with sheep scrapie and 139A. These rodents were chosen because oldfield mice do have the 154N and 169N substitutions, whereas gerbil and spiny mice do not have them. Our results suggest that PrP residues 154 and 169 drive the susceptibility, molecular phenotype and replication rate of prion strains in rodents. This might have implications for the assessment of host range and molecular traceability of prion strains, as well as for the development of improved animal models for prion diseases. Prions are unconventional infectious agents that cause fatal neurodegenerative diseases in animals and humans. A pathological form of the cellular prion protein (PrPC), named PrPSc, appears to be the major or the sole component of prions. These agents are transmitted by inducing the conversion of host PrPC into PrPSc that accumulates in the brain of affected individuals. Different factors are believed to modulate such events, which explains the variable transmission efficiency observed under inter-species experimental inoculation. These factors are still fairly unknown, although evidence exists that some kind of structural compatibility between PrPSc of the infectious inoculum and PrPC of the host has a role in making transmission more or less efficient. We investigated the transmission of prions to different rodents and showed that specific amino acid substitutions (Y154N and S169N) in the prion protein are major determinants of susceptibility to prions. In particular, we showed that these specific variations i) direct the transmission rate of prions between different species in a way that is dependent on the prion strain, ii) affect the molecular characteristics of prions, and iii) influence their replication efficiency.
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DOI：
10.1073/pnas.0409008102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Gossert, AD;Bonjour, S;Wüthrich, K
通讯作者：
Wüthrich, K
影响因子：
64.5
作者：
PRUSINER, SB;SCOTT, M;DEARMOND, SJ
通讯作者：
DEARMOND, SJ
影响因子：
4.8
作者：
Gorfe, Alemayehu A.;Caflisch, Amedeo
通讯作者：
Caflisch, Amedeo
DOI：
10.1073/pnas.0402254101
发表时间：
2004-06-01
影响因子：
11.1
作者：
Govaerts, C;Wille, H;Cohen, FE
通讯作者：
Cohen, FE
影响因子：
4.1
作者：
Cartoni, C;Schininà, ME;Agrimi, U
通讯作者：
Agrimi, U