The protein alpha-synuclein is predominantly expressed in neurons and is associated with neurodegenerative diseases like Parkinson’s disease and dementia with Lewy bodies. However, the normal function of alpha-synuclein in neurons is not clearly defined. We have previously shown that mice lacking alpha-synuclein expression exhibit markedly increased viral growth in the brain, increased mortality and increased neuronal cell death, implicating alpha-synuclein in the neuronal innate immune response. To investigate the mechanism of alpha-synuclein-induced immune responses to viral infections in the brain, we challenged alpha-synuclein knockout mice and human alpha-synuclein knockout dopaminergic neurons with RNA virus infection and discovered that alpha-synuclein is required for neuronal expression of interferon-stimulated genes. Furthermore, human alpha-synuclein knockout neurons treated with type 1 interferon failed to induce a broad range of interferon stimulated genes, implying that alpha-synuclein interacts with type 1 interferon signalling. We next found that alpha-synuclein accumulates in the nucleus of interferon-treated human neurons after interferon treatment and we demonstrated that interferon-mediated phosphorylation of STAT2 is dependent on alpha-synuclein expression in human neurons. Next, we found that activated STAT2 co-localizes with alpha-synuclein following type 1 interferon stimulation in neurons. Finally, we found that brain tissue from patients with viral encephalitis expresses increased levels of phospho-serine129 alpha-synuclein in neurons. Taken together, our results show that alpha-synuclein expression supports neuron-specific interferon responses by localizing to the nucleus, supporting STAT2 activation, co-localizing with phosphorylated STAT2 in neurons and supporting expression of interferon-stimulated genes. These data provide a novel mechanism that links interferon activation and alpha-synuclein function in neurons.

中文翻译：

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α-突触核蛋白支持神经元和脑组织中的 1 型干扰素信号传导


α-突触核蛋白主要在神经元中表达，与帕金森病和路易体痴呆等神经退行性疾病有关。然而，α-突触核蛋白在神经元中的正常功能尚不清楚。我们之前已经证明，缺乏α-突触核蛋白表达的小鼠大脑中的病毒生长显着增加，死亡率增加，神经元细胞死亡增加，这表明α-突触核蛋白参与神经元先天免疫反应。为了研究α-突触核蛋白诱导大脑中病毒感染的免疫反应的机制，我们用RNA病毒感染攻击α-突触核蛋白敲除小鼠和人类α-突触核蛋白敲除多巴胺能神经元，发现α-突触核蛋白是神经元表达干扰素刺激的基因。此外，用 1 型干扰素处理的人 α-突触核蛋白敲除神经元未能诱导广泛的干扰素刺激基因，这意味着 α-突触核蛋白与 1 型干扰素信号传导相互作用。接下来我们发现α-突触核蛋白在干扰素治疗后在经干扰素处理的人类神经元的细胞核中积聚，并且我们证明干扰素介导的STAT2磷酸化依赖于人类神经元中α-突触核蛋白的表达。接下来，我们发现在 1 型干扰素刺激神经元后，激活的 STAT2 与 α-突触核蛋白共定位。最后，我们发现病毒性脑炎患者的脑组织神经元中磷酸丝氨酸 129 α-突触核蛋白的表达水平升高。 综上所述，我们的结果表明，α-突触核蛋白表达通过定位于细胞核、支持 STAT2 激活、与神经元中磷酸化 STAT2 共定位以及支持干扰素刺激基因的表达来支持神经元特异性干扰素反应。这些数据提供了一种将神经元中干扰素激活和α-突触核蛋白功能联系起来的新机制。