Reactive oxygen species (ROS) serve as critical intracellular signaling molecules but in excess can cause oxidative stress and damage organelles and macromolecules, eventually leading to cell death (Zuo et al., 2015). Increased ROS production and oxidative stress have been implicated in the pathogenesis of numerous neurodegenerative conditions, including, among others, Alzheimer’s disease (AD; Behl, 2005), Parkinson’s disease (PD; Trist et al., 2019), Huntington’s disease (HD; Browne and Beal, 2006), Friedrich’s ataxia (Lupoli et al., 2018), multiple sclerosis (MS; Di Filippo et al., 2010), and stroke (Rodrigo et al., 2013). Aging is the primary risk factor for most neurodegenerative diseases, and oxidative stress is known to increase with aging. Although increased oxidative stress is the cumulative result of many factors including changes in tissue antioxidant status, increased mitochondrial dysfunction, and altered metal homeostasis, the majority of the excessive ROS are produced by the mitochondria (Buendia et al., 2016). The endogenous antioxidant response pathway protects cells from oxidative stress by increasing the expression of cytoprotective enzymes that can scavenge free radicals and reduce the risk of cellular damage caused by ROS (Itoh et al., 1997; Motohashi and Yamamoto, 2004; Buendia et al., 2016). The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2, also called NFE2L2) regulates this pathway by binding to antioxidant response elements (AREs) in the promoters of antioxidant genes (Itoh et al., 1997; Motohashi and Yamamoto, 2004). These AREs are cis-acting enhancer sequences. Past studies identified a necessary ARE core sequence of RTGACnnnGC, but this sequence alone is insufficient to mediate induction and requires additional flanking nucleotides that can vary between different AREs (Wasserman and Fahl, 1997).

中文翻译：

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NRF2 作为神经退行性疾病的治疗靶点。

活性氧 (ROS) 作为关键的细胞内信号分子，但过量会导致氧化应激并损伤细胞器和大分子，最终导致细胞死亡（Zuo 等，2015）。增加的 ROS 产生和氧化应激与许多神经退行性疾病的发病机制有关，其中包括阿尔茨海默病（AD；Behl，2005）、帕金森病（PD；Trist 等，2019）、亨廷顿病（HD； Browne 和 Beal，2006 年）、弗里德里希共济失调（Lupoli 等人，2018 年）、多发性硬化症（MS；Di Filippo 等人，2010 年）和中风（Rodrigo 等人，2013 年）。衰老是大多数神经退行性疾病的主要危险因素，已知氧化应激会随着衰老而增加。尽管氧化应激的增加是许多因素的累积结果，包括组织抗氧化状态的变化、线粒体功能障碍的增加和金属稳态的改变，但大多数过量的 ROS 是由线粒体产生的（Buendia 等，2016）。内源性抗氧化反应通路通过增加细胞保护酶的表达来保护细胞免受氧化应激，这些酶可以清除自由基并降低由 ROS 引起的细胞损伤的风险（Itoh 等，1997；Motohashi 和 Yamamoto，2004；Buendia 等。 , 2016)。转录因子核因子类红细胞 2 相关因子 2（NRF2，也称为 NFE2L2）通过与抗氧化基因启动子中的抗氧化反应元件 (ARE) 结合来调节该途径（Itoh 等，1997；Motohashi 和 Yamamoto，2004） . 这些 ARE 是顺式作用增强子序列。过去的研究确定了一个必要的 ARERTGACnnnGC 的核心序列，但仅此序列不足以介导诱导，并且需要额外的侧翼核苷酸，这些核苷酸可以在不同的 ARE 之间变化（Wasserman 和 Fahl，1997）。