Beatman Erica L, Massey Aaron, Shives Katherine D, Burrack Kristina S, Chamanian Mastooreh, Morrison Thomas E, Beckham J David
Department of Medicine, Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA.
Department of Medicine, Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
J Virol. 2015 Dec 30;90(6):2767-82. doi: 10.1128/JVI.02949-15.
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.
Neuroinvasive viruses such as West Nile virus are able to infect neurons and cause severe disease, such as encephalitis, or infection of brain tissue. Following viral infection in the central nervous system, only select neurons are infected, implying that neurons exhibit innate resistance to viral infections. We discovered that native neuronal expression of alpha-synuclein inhibited viral infection in the central nervous system. When the gene for alpha-synuclein was deleted, mice exhibited significantly decreased survival, markedly increased viral growth in the brain, and evidence of increased neuron injury. Virus-induced alpha-synuclein localized to intracellular neuron membranes, and in the absence of alpha-synuclein expression, specific endoplasmic reticulum stress signaling events were significantly increased. We describe a new neuron-specific inhibitor of viral infections in the central nervous system. Given the importance of alpha-synuclein as a cause of Parkinson's disease, these data also ascribe a novel functional role for the native expression of alpha-synuclein in the CNS.
我们发现，α-突触核蛋白（Asyn）在神经元中的天然表达可抑制中枢神经系统（CNS）中的病毒感染、损伤和疾病。包膜RNA病毒，如西尼罗河病毒（WNV），侵入中枢神经系统并引起脑炎，但对于中枢神经系统中病毒感染的先天性神经元特异性抑制剂知之甚少。在原代神经元感染WNV后，我们发现Asyn蛋白表达增加。与野生型和杂合子同窝小鼠相比，Asyn基因敲除小鼠脑中WNV和委内瑞拉马脑炎病毒（VEEV）TC83的感染滴度平均增加了10（4.5）个感染性病毒颗粒。与Asyn杂合子或纯合子对照小鼠相比，Asyn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定位于表达病毒包膜蛋白和内质网（ER）相关转运蛋白Rab1的核周神经元区域。在Asyn基因敲除的原代神经元培养物中，与表达Asyn的原代神经元培养物相比，已知支持WNV复制的ER信号通路的表达水平在病毒感染之前和期间显著升高。我们提出了一个模型，其中病毒诱导的Asyn定位于ER衍生的膜上，调节病毒诱导的ER应激信号，并抑制中枢神经系统中的病毒复制、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种新的重要功能作用，α-突触核蛋白是一种与帕金森病发展密切相关的蛋白质。
西尼罗河病毒等嗜神经性病毒能够感染神经元并导致严重疾病，如脑炎或脑组织感染。在中枢神经系统发生病毒感染后，只有特定的神经元被感染，这意味着神经元对病毒感染具有先天性抵抗力。我们发现α-突触核蛋白在神经元中的天然表达可抑制中枢神经系统中的病毒感染。当α-突触核蛋白基因被删除时，小鼠的存活率显著降低，脑中病毒生长明显增加，并且有神经元损伤增加的证据。病毒诱导的α-突触核蛋白定位于细胞内神经元膜上，并且在缺乏α-突触核蛋白表达的情况下，特定的内质网应激信号事件显著增加。我们描述了一种中枢神经系统中新型的病毒感染神经元特异性抑制剂。鉴于α-突触核蛋白作为帕金森病病因的重要性，这些数据也赋予了α-突触核蛋白在中枢神经系统中天然表达的新功能作用。
