Drolet Jennifer, Buchner-Duby Brodie, Stykel Morgan G, Coackley Carla, Kang Jing X, Ma David W L, Ryan Scott D
Department of Molecular and Cellular Biology, The University of Guelph, Guelph, ON N1G 2W1, Canada.
Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129.
Mol Biol Cell. 2021 Apr 1;32(7):511-520. doi: 10.1091/mbc.E20-09-0599. Epub 2021 Jan 27.
Evidence suggests that n-3 polyunsaturated fatty acids may act as activators of the Nrf2 antioxidant pathway. The antioxidant response, in turn, promotes neuronal differentiation and neurite outgrowth. Nrf2 has recently been suggested to be a cell intrinsic mediator of docosohexanoic acid (DHA) signaling. In the current study, we assessed whether DHA-mediated axodendritic development was dependent on activation of the Nrf2 pathway and whether Nrf2 protected from agrochemical-induced neuritic retraction. Expression profiling of the DHA-enriched mouse brain relative to wild type showed a significant enrichment of genes associated with neuronal development and neuronal projection and genes associated with the Nrf2-transcriptional pathway. Moreover, we found that primary cortical neurons treated with DHA showed a dose-dependent increase in Nrf2 transcriptional activity and Nrf2-target gene expression. DHA-mediated activation of Nrf2 promoted neurite outgrowth and inhibited oxidative stress-induced neuritic retraction evoked by exposure to agrochemicals. Finally, we provide evidence that this effect is largely dependent on induction of the Nrf2-target gene NAD(P)H: (quinone acceptor) oxidoreductase 1 (NQO1), and that silencing of either or blocks the effects of DHA on the axodendritic compartment. Collectively, these data support a role for the Nrf2-NQO1 pathway in DHA-mediated axodendritic development and protection from agrochemical exposure.
有证据表明，n-3多不饱和脂肪酸可能作为Nrf2抗氧化途径的激活剂。反过来，抗氧化反应会促进神经元分化和神经突生长。最近有人提出，Nrf2是二十二碳六烯酸（DHA）信号传导的细胞内源性介质。在本研究中，我们评估了DHA介导的轴突树突发育是否依赖于Nrf2途径的激活，以及Nrf2是否能保护神经元免受农用化学品诱导的神经突回缩。与野生型相比，富含DHA的小鼠大脑的表达谱显示，与神经元发育和神经元投射相关的基因以及与Nrf2转录途径相关的基因显著富集。此外，我们发现用DHA处理的原代皮质神经元的Nrf2转录活性和Nrf2靶基因表达呈剂量依赖性增加。DHA介导的Nrf2激活促进了神经突生长，并抑制了由农用化学品暴露引起的氧化应激诱导的神经突回缩。最后，我们提供的证据表明，这种作用很大程度上依赖于Nrf2靶基因NAD(P)H:（醌受体）氧化还原酶1（NQO1）的诱导，并且敲低NQO1或Nrf2会阻断DHA对轴突树突区室的影响。总的来说，这些数据支持Nrf2-NQO1途径在DHA介导的轴突树突发育以及免受农用化学品暴露的保护作用中发挥作用。
