Wu Yan, Li Pengfei, Liu Liu, Goodwin Andrew J, Halushka Perry V, Hirose Tetsuro, Nakagawa Shinichi, Zhou Jiliang, Liu Meng, Fan Hongkuan
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Mol Ther. 2022 Jul 6;30(7):2618-2632. doi: 10.1016/j.ymthe.2022.03.011. Epub 2022 Mar 21.
Sepsis-associated encephalopathy (SAE) is characterized by acute and diffuse brain dysfunction and correlates with long-term cognitive impairments with no targeted therapy. We used a mouse model of sepsis-related cognitive impairment to examine the role of lncRNA nuclear enriched abundant transcript 1 (Neat1) in SAE. We observed that Neat1 expression was increased in neuronal cells from septic mice and that it directly interacts with hemoglobin subunit beta (Hbb), preventing its degradation. The Neat1/Hbb axis suppressed postsynaptic density protein 95 (PSD-95) levels and decreased dendritic spine density. Neat1 knockout mice exhibited decreased Hbb levels, which resulted in increased PSD-95 levels, increased neuronal dendritic spine density, and decreased anxiety and memory impairment. Neat1 silencing via the antisense oligonucleotide GapmeR ameliorated anxiety-like behavior and cognitive impairment post-sepsis. In conclusion, we uncovered a previously unknown mechanism of the Neat1/Hbb axis in regulating neuronal dysfunction, which may lead to a novel treatment strategy for SAE.
脓毒症相关性脑病（SAE）的特征是急性弥漫性脑功能障碍，且与长期认知障碍相关，目前尚无针对性治疗方法。我们使用脓毒症相关认知障碍的小鼠模型来研究长链非编码RNA核富集丰富转录本1（Neat1）在SAE中的作用。我们观察到，脓毒症小鼠神经元细胞中Neat1表达增加，且它直接与血红蛋白亚基β（Hbb）相互作用，阻止其降解。Neat1/Hbb轴抑制了突触后致密蛋白95（PSD-95）水平，并降低了树突棘密度。Neat1基因敲除小鼠的Hbb水平降低，导致PSD-95水平升高、神经元树突棘密度增加，以及焦虑和记忆障碍减轻。通过反义寡核苷酸GapmeR沉默Neat1可改善脓毒症后的焦虑样行为和认知障碍。总之，我们发现了Neat1/Hbb轴调节神经元功能障碍的一种前所未知的机制，这可能会为SAE带来一种新的治疗策略。
