The N-Terminal Polybasic Region of Prion Protein Is Crucial in Prion Pathogenesis Independently of the Octapeptide Repeat Region
The N-Terminal Polybasic Region of Prion Protein Is Crucial in Prion Pathogenesis Independently of the Octapeptide Repeat Region
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DOI：
10.1007/s12035-019-01804-5
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发表时间：
2019-11-09
影响因子：
5.1
通讯作者：
Sakaguchi, Suehiro
中科院分区：
文献类型：
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作者：
Das, Nandita Rani;Miyata, Hironori;Sakaguchi, Suehiro
朊病毒蛋白的细胞亚型（称为 PrP）构象转变为异常折叠的淀粉样变亚型 PrPSc，是朊病毒疾病的重要致病事件。然而，确切的转换机制仍然很大程度上未知。一系列证据表明，N 端结构域（包括 N 端、带正电荷的多碱基区和八肽重复 (OR) 区）对于 PrP 在感染朊病毒后转化为 PrPSc 非常重要。为了进一步了解多碱基区和 OR 区在朊病毒发病机制中的作用，我们生成了两种不同的转基因小鼠，命名为 Tg(PrP3K3A)/Prnp(0/0) 和 Tg(PrP3K3A 增量 OR)/Prnp(0/0) 小鼠，它们在多碱基区突变的密码子 23、24 和 27 处表达带有赖氨酸残基的 PrP分别在 Prnp(0/0) 背景上删除或不删除 OR 区域，并在脑内接种 RML 和 22L 朊病毒。我们发现 Tg(PrP3K3A)/Prnp(0/0) 小鼠对朊病毒具有高度抵抗力，这表明 23、24 和 27 处的赖氨酸残基对于支持朊病毒感染的多碱基区域可能很重要。 Tg(PrP3K3A增量OR)/Prnp(0/0)小鼠对RML和22L朊病毒的敏感性也降低，相当于Tg(PrP3K3A)/Prnp(0/0)小鼠。 PrP3K3A增量OR的前OR区域，包括多碱基区域，但不是PrP3K3A，在转换为PrP(Sc)3K3A增量OR期间异常地转变为蛋白酶抗性结构。这些结果表明，虽然 OR 区域可能在 PrP 转化为 PrPSc 过程中影响多碱基区域的构象，但多碱基区域可以独立于 OR 区域在朊病毒发病机制中发挥关键作用。
Conformational conversion of the cellular isoform of prion protein, designated PrP, into the abnormally folded, amyloidogenic isoform, PrPSc, is an essential pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Lines of evidence indicate that the N-terminal domain, which includes the N-terminal, positively charged polybasic region and the octapeptide repeat (OR) region, is important for PrP to convert into PrPSc after infection with prions. To further gain insights into the role of the polybasic region and the OR region in prion pathogenesis, we generated two different transgenic mice, designated Tg(PrP3K3A)/Prnp(0/0) and Tg(PrP3K3A increment OR)/Prnp(0/0) mice, which express PrP with lysine residues at codons 23, 24, and 27 in the polybasic region mutated with or without a deletion of the OR region on the Prnp(0/0) background, respectively, and intracerebrally inoculated them with RML and 22L prions. We show that Tg(PrP3K3A)/Prnp(0/0) mice were highly resistant to the prions, indicating that lysine residues at 23, 24, and 27 could be important for the polybasic region to support prion infection. Tg(PrP3K3A increment OR)/Prnp(0/0) mice also had reduced susceptibility to RML and 22L prions equivalent to Tg(PrP3K3A)/Prnp(0/0) mice. The pre-OR region, including the polybasic region, of PrP3K3A increment OR, but not PrP3K3A, was unusually converted to a protease-resistant structure during conversion to PrP(Sc)3K3A increment OR. These results suggest that, while the OR region could affect the conformation of the polybasic region during conversion of PrP into PrPSc, the polybasic region could play a crucial role in prion pathogenesis independently of the OR region.