The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration.
The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration.
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DOI：
10.1196/annals.1427.036
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发表时间：
2008-12
影响因子：
5.2
通讯作者：
Chen, Pei-Chun
中科院分区：
文献类型：
--
作者：
Johnson, Jeffrey A.;Johnson, Delinda A.;Kraft, Andrew D.;Calkins, Marcus J.;Jakel, Rebekah J.;Vargas, Marcelo R.;Chen, Pei-Chun
保护性基因的转录激活是由一种称为抗氧化反应元件(ARE)的顺式作用元件介导的。转录因子Nrf2(核因子-E2相关因子2)与ARE结合。该通路的激活保护细胞免受氧化应激诱导的细胞死亡。在阿尔茨海默病、帕金森氏病、亨廷顿病和肌萎缩侧索硬化症等多种慢性神经退行性疾病的发病过程中，氧化应激增加与神经细胞死亡有关。我们假设，NRF2-ARE激活是一种新的神经保护途径，可以抵抗各种与氧化应激相关的神经退行性损伤。在最近的研究中，用NRF2-ARE途径的化学激活剂处理的原代神经元培养细胞对氧化应激诱导的神经毒性表现出显著的抵抗力。从ARE-HPAP报告鼠产生的类似培养表明，星形胶质细胞中Nrf2-ARE途径被选择性激活，这表明星形胶质细胞中Nrf2的激活以某种方式赋予了对幼稚神经元的抵抗。此外，在神经退化的化学模型中，Nrf2基因敲除小鼠对线粒体复合体I和II抑制剂明显更敏感。结合这些观察结果，以及星形胶质细胞是Nrf2-Are介导的神经保护的中枢的结果，我们将Nrf2过表达的星形胶质细胞移植到小鼠纹状体内，然后用丙二酸进行损伤。这一过程导致了对丙二酸诱导的神经毒性的戏剧性保护。我们将讨论如何将其转化为神经退变的其他化学和遗传模型。
Transcriptional activation of protective genes is mediated by a cis-acting element called the antioxidant responsive element (ARE). The transcription factor Nrf2 (NF-E2-related factor 2) binds to the ARE. Activation of this pathway protects cells from oxidative stress-induced cell death. Increased oxidative stress is associated with neuronal cell death during the pathogenesis of multiple chronic neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. We hypothesize that Nrf2-ARE activation is a novel neuroprotective pathway that confers resistance to a variety of oxidative stress-related neurodegenerative insults. In recent studies, primary neuronal cultures treated with chemical activators of the Nrf2-ARE pathway displayed significantly greater resistance to oxidative stress induced neurotoxicity. Similar cultures generated from ARE-hPAP reporter mice demonstrated selective activation of the Nrf2-ARE pathway in astrocytes suggesting that Nrf2 activation in astrocytes somehow confers resistance to naïve neurons. Further, in chemical models of neurodegeneration, Nrf2 knockout mice are significantly more sensitive to mitochondrial complex I and II inhibitors. Combining these observations with the results implying that the astrocyte is central to Nrf2-ARE mediated neuroprotection, we transplanted Nrf2-overexpressing astrocytes into the mouse striatum prior to lesioning with malonate. This procedure led to dramatic protection against malonate-induced neurotoxicity. Translating this to other chemical and genetic models of neurodegeneration will be discussed.
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影响因子：
4.7
作者：
Kraft, Andrew D.;Lee, Jong-Min;Johnson, Jeffrey A.
通讯作者：
Johnson, Jeffrey A.
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M
DOI：
10.1073/pnas.93.24.13943
发表时间：
1996-11-26
影响因子：
11.1
作者：
Chan, KM;Lu, RH;Kan, YW
通讯作者：
Kan, YW
DOI：
10.1006/bbrc.1997.6943
发表时间：
1997-07-18
影响因子：
3.1
作者：
Itoh, K;Chiba, T;Nabeshima, Y
通讯作者：
Nabeshima, Y
DOI：
10.1073/pnas.0505723102
发表时间：
2006-01-17
影响因子：
11.1
作者：
Satoh, T;Okamoto, SI;Lipton, SA
通讯作者：
Lipton, SA