Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain
Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain
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DOI：
10.1128/jvi.02949-15
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发表时间：
2016-03-01
影响因子：
5.4
通讯作者：
Beckham, J. David
中科院分区：
文献类型：
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作者：
Beatman, Erica L.;Massey, Aaron;Beckham, J. David
我们已经发现，α-突触核蛋白(Asyn)的天然神经元表达可以抑制中枢神经系统(CNS)中的病毒感染、损伤和疾病。被包裹的RNA病毒，如西尼罗河病毒(West Nile Virus，WNV)，入侵中枢神经系统并引起脑炎，但对中枢神经系统病毒感染的天然神经元特异性抑制因子知之甚少。在西尼罗河病毒感染原代神经元后，我们发现Asyn蛋白表达增加。与野生型和杂合子小鼠相比，非同步基因敲除小鼠大脑中WNV和委内瑞拉马脑炎病毒(VEEV)TC83的感染性滴度平均增加了10(4.5)个感染性病毒颗粒。与非同步杂合子或纯合子对照小鼠相比，非同步基因敲除小鼠的病毒诱导死亡率也显著增加。病毒诱导的Asyn定位于核周、神经元区域，表达病毒包膜蛋白和内质网(ER)相关运输蛋白Rab1。在非同步基因敲除的原代神经元培养中，支持WNV复制的ER信号通路的表达水平在病毒感染前和感染期间显著高于表达非同步基因的原代神经元培养中的表达水平。我们提出了一个模型，在该模型中，病毒诱导的Asyn定位于内质网衍生的膜，调节病毒诱导的内质网应激信号，并抑制病毒在中枢神经系统的复制、生长和损伤。这些数据为天然α-突触核蛋白的表达提供了一个新的和重要的功能作用，这是一种与帕金森病的发展密切相关的蛋白质。
We have discovered that native, neuronal expression of alpha-synuclein (Asyn) inhibits viral infection, injury, and disease in the central nervous system (CNS). Enveloped RNA viruses, such as West Nile virus (WNV), invade the CNS and cause encephalitis, yet little is known about the innate neuron-specific inhibitors of viral infections in the CNS. Following WNV infection of primary neurons, we found that Asyn protein expression is increased. The infectious titer of WNV and Venezuelan equine encephalitis virus (VEEV) TC83 in the brains of Asyn-knockout mice exhibited a mean increase of 10(4.5) infectious viral particles compared to the titers in wild-type and heterozygote littermates. Asyn-knockout mice also exhibited significantly increased virus-induced mortality compared to Asyn heterozygote or homozygote control mice. Virus-induced Asyn localized to perinuclear, neuronal regions expressing viral envelope protein and the endoplasmic reticulum (ER)-associated trafficking protein Rab1. In Asyn-knockout primary neuronal cultures, the levels of expression of ER signaling pathways, known to support WNV replication, were significantly elevated before and during viral infection compared to those in Asyn-expressing primary neuronal cultures. We propose a model in which virus-induced Asyn localizes to ER-derived membranes, modulates virus-induced ER stress signaling, and inhibits viral replication, growth, and injury in the CNS. These data provide a novel and important functional role for the expression of native alpha-synuclein, a protein that is closely associated with the development of Parkinson's disease.