Lv Qiankun, Zhong Zhen, Hu Binbin, Yan Si, Yan Yufang, Zhang Junjun, Shi Ting, Jiang Lijuan, Li Wen, Huang Wei
Department of Neurology, the Second Affiliated Hospital of Nanchang University, Nanchang, China.
J Neurochem. 2021 May;157(3):599-610. doi: 10.1111/jnc.15299. Epub 2021 Feb 2.
Parkinson disease (PD) is a neurodegenerative disease characterized by selective loss of dopaminergic (DA) neurons in the midbrain. The regulatory role of a variety of microRNAs in PD has been confirmed, and our study is the first to demonstrate that miR-3473b is involved in the regulation of PD. In vitro, an miR-3473b inhibitor can inhibit the secretion of inflammatory factors (TNF-α and IL-1β) in moues microglia cell line (BV2) cells induced by lipopolysaccharide (LPS) and promote autophagy in BV2 cells. In vivo, miR-3473b antagomir can inhibit the activation of substantia nigra pars compacta (SNpc) microglia of C57BL/6 mice induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and promote autophagy. Deletion of TREM2, one of the most highly expressed receptors in microglia, leads to the occurrence and development of PD. ULK1 is a component of the Atg1 complex. Deletion of ULK1 aggravates the pathological reaction of PD. TREM2 and ULK1 are predicted potential targets of miR-3473b by Targetscan. Then, the results of our experiments indicate that transfection with a miR-3473b mimic can inhibit the expression of TREM2 and ULK1. Data from a double luciferase experiment indicate that the 3'-UTR of TREM2, but not ULK1, is the direct target of miR-3473b. Then we aim to investigate the regulation of TREM2 and ULK1 in PD. We found that the expression of p-ULK1 was significantly increased via up-regulation of TREM2. The increased expression of p-ULK1 can promote autophagy and inhibit the expression of inflammatory factors. The regulation of ULK1 by miR-3473b may be accomplished indirectly through TREM2. Thus, miR-3473b may regulate the secretion of proinflammatory mediators by targeting TREM2/ULK1 expression to regulate the role of autophagy in the pathogenesis of inflammation in Parkinson's disease, suggesting that mir-3473b may be a potential therapeutic target to regulate the inflammatory response in PD.
帕金森病（PD）是一种神经退行性疾病，其特征是中脑多巴胺能（DA）神经元选择性丧失。多种微小RNA在帕金森病中的调节作用已得到证实，而我们的研究首次证明miR-3473b参与帕金森病的调节。在体外，miR-3473b抑制剂可抑制脂多糖（LPS）诱导的小鼠小胶质细胞系（BV2）细胞中炎性因子（TNF-α和IL-1β）的分泌，并促进BV2细胞中的自噬。在体内，miR-3473b拮抗剂可抑制1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的C57BL/6小鼠黑质致密部（SNpc）小胶质细胞的激活并促进自噬。小胶质细胞中表达最高的受体之一TREM2的缺失会导致帕金森病的发生和发展。ULK1是Atg1复合物的一个组成部分。ULK1的缺失会加重帕金森病的病理反应。通过Targetscan预测TREM2和ULK1是miR-3473b的潜在靶标。然后，我们的实验结果表明，转染miR-3473b模拟物可抑制TREM2和ULK1的表达。双荧光素酶实验数据表明，TREM2的3'-UTR而非ULK1的3'-UTR是miR-3473b的直接靶标。然后我们旨在研究TREM2和ULK1在帕金森病中的调节作用。我们发现，通过上调TREM2，p-ULK1的表达显著增加。p-ULK1表达的增加可促进自噬并抑制炎性因子的表达。miR-3473b对ULK1的调节可能是通过TREM2间接完成的。因此，miR-3473b可能通过靶向TREM2/ULK1的表达来调节促炎介质的分泌，从而调节自噬在帕金森病炎症发病机制中的作用，这表明miR-3473b可能是调节帕金森病炎症反应的潜在治疗靶点。
