PDF(Pubmed)
Abstract：
Neurologic manifestations are an immediate consequence of SARS-CoV-2 infection, the etiologic agent of COVID-19, which, however, may also trigger long-term neurological effects. Notably, COVID-19 patients with neurological symptoms show elevated levels of biomarkers associated with brain injury, including Tau proteins linked to Alzheimer\'s pathology. Studies in brain organoids revealed that SARS-CoV-2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to the recruitment of Tau into stress granules (SGs) operated by the nucleocapsid protein (NCAP) of SARS-CoV-2. To test this hypothesis, we investigated whether NCAP interacts with Tau and localizes to SGs in hippocampal neurons in vitro and in vivo. Mechanistically, we tested whether SUMOylation, a posttranslational modification of NCAP and Tau, modulates their distribution in SGs and their pathological interaction. We found that NCAP and Tau colocalize and physically interact. We also found that NCAP induces hyperphosphorylation of Tau and causes cognitive impairment in mice infected with NCAP in their hippocampus. Finally, we found that SUMOylation modulates NCAP SG formation in vitro and cognitive performance in infected mice. Our data demonstrate that NCAP induces Tau pathological changes both in vitro and in vivo. Moreover, we demonstrate that SUMO2 ameliorates NCAP-induced Tau pathology, highlighting the importance of the SUMOylation pathway as a target of intervention against neurotoxic insults, such as Tau oligomers and viral infection.
摘要：
神经系统表现是SARS-CoV-2感染的直接后果，COVID-19的病原体，然而,也可能引发长期的神经影响。值得注意的是,有神经症状的COVID-19患者显示与脑损伤相关的生物标志物水平升高，包括与阿尔茨海默氏症病理有关的Tau蛋白。脑类器官的研究表明，SARS-CoV-2改变了Tau在受感染神经元中的磷酸化和分布，但机制目前尚不清楚。我们假设这些病理变化是由于Tau被募集到由SARS-CoV-2的核衣壳蛋白（NCAP）操作的应激颗粒（SGs）中。为了检验这个假设，我们在体外和体内研究了NCAP是否与Tau相互作用并定位到海马神经元中的SGs。机械上,我们测试了SUMOylation，NCAP和Tau的翻译后修饰，调节它们在SGs中的分布及其病理相互作用。我们发现NCAP和Tau共定位和物理相互作用。我们还发现NCAP诱导Tau的过度磷酸化，并在海马中感染NCAP的小鼠中引起认知障碍。最后,我们发现SUMO化调节NCAP体外SG形成和感染小鼠的认知能力.我们的数据表明，NCAP在体外和体内均可诱导Tau病理变化。此外，我们证明SUMO2改善NCAP诱导的Tau病理，强调SUMO化途径作为神经毒性损伤干预目标的重要性，如Tau寡聚体和病毒感染。
