A molecular switch controls interspecies prion disease transmission in mice
A molecular switch controls interspecies prion disease transmission in mice
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DOI：
10.1172/jci42051
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发表时间：
2010-07-01
影响因子：
15.9
通讯作者：
Aguzzi, Adriano
中科院分区：
文献类型：
--
作者：
Sigurdson, Christina J.;Nilsson, K. Peter R.;Aguzzi, Adriano
传染性海绵状脑病是一种致命的神经退行性疾病，表现为细胞朊蛋白（PrPC）的聚集形式，称为PrPSc。不同物种的朊病毒对异种宿主的传染性差异很大。可变的传输障碍取决于传入的PrPSc和主机PrPC之间的序列差异，此外，应变依赖的构象特性的PrPSc。PrPC内的β（2）-α（2）环区域在物种之间变化很大，其结构受到2个氨基酸序列位置170（最常见的是S或N）和174（N或T）中残基类型的影响。在这项研究中，我们接种朊病毒从5个不同的物种到转基因小鼠表达无序环或刚性环的PrPC变体。相似的β 2-α 2环结构与有效的传输相关，而不同的环与强传输障碍相关。然后，我们根据170 S/N多态性对跨物种传播的文献数据进行分类。在170位氨基酸残基相同的物种之间的传输屏障一般较低，而在具有不同残基的物种之间的传输屏障则较高。这些发现指出了朊病毒在不同物种之间传播的局部β 2-α 2环结构的触发作用。
Transmissible spongiform encephalopathies are lethal neurodegenerative disorders that present with aggregated forms of the cellular prion protein (PrPC), which are known as PrPSc. Prions from different species vary considerably in their transmissibility to xenogeneic hosts. The variable transmission barriers depend on sequence differences between incoming PrPSc and host PrPC and additionally, on strain-dependent conformational properties of PrPSc. The beta(2)-alpha(2) loop region within PrPC varies substantially between species, with its structure being influenced by the residue types in the 2 amino acid sequence positions 170 (most commonly S or N) and 174 (N or T). In this study, we inoculated prions from 5 different species into transgenic mice expressing either disordered-loop or rigid-loop PrPC variants. Similar beta 2-alpha 2 loop structures correlated with efficient transmission, whereas dissimilar loops correlated with strong transmission barriers. We then classified literature data on cross-species transmission according to the 170S/N polymorphism. Transmission barriers were generally low between species with the same amino acid residue in position 170 and high between those with different residues. These findings point to a triggering role of the local beta 2-alpha 2 loop structure for prion transmissibility between different species.