Wang Qingqing, Ren Nan, Cai Zhipeng, Lin Qingxia, Wang Zhangjing, Zhang Qunwei, Wu Siying, Li Huangyuan
Department of Preventive Medicine, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, 350122 Fuzhou, China.
Zhangzhou Entry-Exit Inspection and Quarantine Bureau, Shicangduan, Shuixian Street, 363000 Zhangzhou, China.
NPJ Parkinsons Dis. 2017 Oct 20;3:31. doi: 10.1038/s41531-017-0033-1. eCollection 2017.
Both transcription factors (TFs) and microRNAs (miRNAs) can exert a widespread impact on gene expression. In the present study, we investigated the role of Nrf2 in paraquat-induced intracorporeal neurodegeneration and miRNA expression by exposing Nrf2 wild-type and knockout mice to paraquat (PQ) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Exposure to 10 mg/kg PQ or 30 mg/kg MPTP caused damage to nerve cells in the substantia nigra (SN) in both Nrf2 (+/+) and Nrf2 (-/-) ICR mice, which included cell morphological changes, detectable apoptosis and a significant reduction in the number of dopaminergic (DA) neurons. When mice were exposed to the same PQ dose of 10 mg/kg, significant fewer tyrosine hydroxylase (TH)-positive DA neurons were observed in the Nrf2 (-/-) mice than that in the Nrf2 (+/+) mice. Both Nrf2 deficiency and PQ or MPTP exposure could alter miRNA expression profile in the SN, suggesting the potential involvement of Nrf2 in the PQ-induced or MPTP-induced miRNA expression alteration. The expression of miR-380-3p was altered by the Nrf2-MPTP interaction effect. miR-380-3p/Sp3-mRNA pathway is likely part of the mechanism of MPTP-induced neurodegeneration. Collectively, our results corroborated the protective role of Nrf2 and also demonstrated the essential interaction of Nrf2 with miRNAs in intracorporal neurodegeneration induced by neurotoxicants.
转录因子（TFs）和微小RNA（miRNAs）均可对基因表达产生广泛影响。在本研究中，我们通过将Nrf2野生型和敲除小鼠暴露于百草枯（PQ）或1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），研究了Nrf2在百草枯诱导的体内神经退行性变和miRNA表达中的作用。暴露于10mg/kg PQ或30mg/kg MPTP会导致Nrf2（+/+）和Nrf2（-/-）ICR小鼠黑质（SN）中的神经细胞受损，包括细胞形态变化、可检测到的细胞凋亡以及多巴胺能（DA）神经元数量的显著减少。当小鼠暴露于相同剂量10mg/kg的PQ时，Nrf2（-/-）小鼠中观察到的酪氨酸羟化酶（TH）阳性DA神经元明显少于Nrf2（+/+）小鼠。Nrf2缺乏以及PQ或MPTP暴露均可改变SN中的miRNA表达谱，提示Nrf2可能参与PQ或MPTP诱导的miRNA表达改变。miR-380-3p的表达受Nrf2-MPTP相互作用效应的影响。miR-380-3p/Sp3-mRNA通路可能是MPTP诱导神经退行性变机制的一部分。总体而言，我们的结果证实了Nrf2的保护作用，同时也证明了Nrf2与miRNAs在神经毒物诱导的体内神经退行性变中的重要相互作用。
