LncRNA MALAT1 facilitates inflammasome activation via epigenetic suppression of Nrf2 in Parkinson's disease.
LncRNA MALAT1 facilitates inflammasome activation via epigenetic suppression of Nrf2 in Parkinson's disease.
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DOI：
10.1186/s13041-020-00656-8
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发表时间：
2020-09-24
期刊：
影响因子：
3.6
通讯作者：
Tian JY
中科院分区：
文献类型：
--
作者：
Cai LJ;Tu L;Huang XM;Huang J;Qiu N;Xie GH;Liao JX;Du W;Zhang YY;Tian JY
本研究的目的是阐明长链非编码RNA转移相关肺腺癌转录本1（lncRNA MALAT 1）促进帕金森病（PD）炎症的机制。用1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导C57 BL/6小鼠PD，免疫组化法检测酪氨酸羟化酶（TH）的表达。进行蛋白质印迹和qPCR分析以分别评估蛋白质和mRNA水平的表达。采用脂多糖/三磷酸腺苷（LPS/ATP）体外激活小胶质细胞。通过染色质免疫沉淀（ChIP）、RNA下拉和RNA免疫沉淀芯片（RIP）分析来研究特异性分子之间的相互作用。使用3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四唑（MTT）测定来评估细胞活力和增殖。染色后用流式细胞仪分析细胞凋亡情况。采用二氯荧光素二乙酸酯（DCFH-DA）测定法测定细胞内活性氧（ROS）的产生。结果表明，MALAT 1在MPTP诱导的PD模型小鼠脑组织和LPS/ATP诱导的小胶质细胞中高表达。MALAT 1的敲低抑制核因子（红细胞衍生2）样2因子（NRF 2）表达的升高，从而抑制炎性小体活化和ROS产生。MALAT 1通过募集Zeste同源物增强子2（EZH 2）至NRF 2启动子，抑制Nrf 2表达，从而促进神经炎症。总之，MALAT 1表观遗传学抑制NRF 2，从而诱导PD小鼠和小胶质细胞模型中的炎性体活化和活性氧（ROS）产生。
The goal of the present study was to elucidate the mechanism by which long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) promotes inflammation in Parkinson’s disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to induce PD development in C57BL/6 mice, and tyrosine hydroxylase (TH) expression was analysed by immunohistochemical analysis. Western blot and qPCR analyses were conducted to assess the expression of protein and mRNA levels, respectively. Lipopolysaccharide/adenosine triphosphate (LPS/ATP) was used to activate microglia in vitro. Chromatin immunoprecipitation (ChIP), RNA pull-down and RNA immunoprecipitation chip (RIP) assays were performed to investigate the interaction among specific molecules. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate cell viability and proliferation. Flow cytometry was performed to analyse cell apoptosis after staining. The dichlorofluorescein diacetate (DCFH-DA) assay was used to measure the generation of reactive oxygen species (ROS) in cells. The results showed that MALAT1 was highly expressed in the brains of MPTP-induced PD model mice and in LPS/ATP-induced microglia cells. Knockdown of MALAT1 inhibited elevated nuclear factor (erythroid-derived 2)-like-2 factor (NRF2) expression, thereby inhibiting inflammasome activation and ROS production. MALAT1 was shown to promote neuroinflammation by recruiting enhancer of zeste homologue 2 (EZH2) to the promoter of NRF2, suppressing Nrf2 expression. In summary, MALAT1 epigenetically inhibits NRF2, thereby inducing inflammasome activation and reactive oxygen species (ROS) production in PD mouse and microglial cell models.
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