Department of Preventive Medicine, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, China; Department of Endemic Disease Prevention and Control, Fujian Center For Disease Control & Prevention, Fuzhou 350122, China.
Department of Preventive Medicine, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, China.
Toxicol Lett. 2018 Jul;291:11-28. doi: 10.1016/j.toxlet.2018.04.002. Epub 2018 Apr 5.
Parkinson's disease (PD) is a common age-related degenerative disease of the central nervous system caused mainly by hereditary, pesticides, metals, and polychlorinated biphenyls. Paraquat (PQ), a widely used herbicide, causes PD. Long noncoding RNAs (lncRNAs) are nonprotein-coding transcripts, expressed in the brain and play irreplaceable roles in neurodegenerative diseases. NF-E2-related factor-2 (Nrf2) is an important genetic transcription regulator in oxidative stress. We aimed to discover novel PQ or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-Nrf2-related lncRNAs and explore their association with PD. 17157 lncRNAs and 13707 mRNAs (fold change ≥2, P < 0.05) were identified by Microarray. And the expressions of six lncRNAs were confirmed by using qRT-PCR and two by FISH. Coding-noncoding analysis and qRT-PCR were applied to discover the functions of lncRNAs and predict the targeted genes. In mice, PQ and MPTP exposure caused alteration of the lncRNA expression profile, suggesting lncRNAs may be involved in PQ- and MPTP-induced neurotoxicity. The changes in their lncRNA expression were distinct but related. PQ caused lncRNA expression profiling alteration in the substantia nigra (SN) through an interaction with Nrf2, thus changing the NR_027648/Zc3h14/Cybb and NR_030777/Zfp326/Cpne5 mRNA pathways. Similarly, MPTP caused lncRNA expression profiling alteration in SN through an interaction with Nrf2. Nrf2 may be involved in the development of neurodegeneration induced by PQ and MPTP via interaction with lncRNAs as the molecular mechanism. Our findings indicate the potential roles of lncRNAs in the development of PD by PQ or MPTP and provide positive insights into future mechanism studies.
帕金森病（PD）是一种常见的与年龄相关的中枢神经系统退行性疾病，主要由遗传、农药、金属和多氯联苯引起。百草枯（PQ）是一种广泛使用的除草剂，会导致 PD。长链非编码 RNA（lncRNA）是一种非蛋白编码转录物，在大脑中表达，并在神经退行性疾病中发挥不可替代的作用。核因子-2 相关因子 2（Nrf2）是氧化应激中重要的遗传转录调节因子。我们旨在发现新的 PQ 或 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）-Nrf2 相关 lncRNA，并探讨其与 PD 的关系。通过微阵列鉴定了 17157 个 lncRNA 和 13707 个 mRNA（倍数变化≥2，P<0.05）。并通过 qRT-PCR 和 FISH 验证了六种 lncRNA 的表达。通过编码非编码分析和 qRT-PCR 发现 lncRNA 的功能，并预测其靶向基因。在小鼠中，PQ 和 MPTP 暴露导致 lncRNA 表达谱的改变，提示 lncRNA 可能参与 PQ 和 MPTP 诱导的神经毒性。它们的 lncRNA 表达变化虽然不同，但存在关联。PQ 通过与 Nrf2 相互作用导致黑质（SN）中的 lncRNA 表达谱改变，从而改变 NR_027648/Zc3h14/Cybb 和 NR_030777/Zfp326/Cpne5 mRNA 途径。同样，MPTP 通过与 Nrf2 相互作用导致 SN 中的 lncRNA 表达谱改变。Nrf2 可能通过与 lncRNA 相互作用，参与 PQ 和 MPTP 诱导的神经退行性变的发生，作为分子机制。我们的研究结果表明，lncRNA 可能通过 PQ 或 MPTP 参与 PD 的发生，为未来的机制研究提供了积极的思路。
