NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons

被引:270
作者
Lee, JM
Shih, AY
Murphy, TH
Johnson, JA
机构
[1] Univ Wisconsin, Sch Pharm, Madison, WI 53705 USA
[2] Univ Wisconsin, Mol & Environm Toxicol Ctr, Madison, WI 53705 USA
[3] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA
[4] Univ Wisconsin, Ctr Neurosci, Madison, WI 53705 USA
[5] Univ British Columbia, Dept Psychiat, Vancouver, BC V6T 1Z3, Canada
[6] Univ British Columbia, Dept Physiol, Kinsmen Lab Neurol Res, Vancouver, BC V6T 1Z3, Canada
关键词
D O I
10.1074/jbc.M305204200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
NF-E2-related factor-2 (Nrf2) regulates the gene expression of phase II detoxification enzymes and antioxidant proteins through an enhancer sequence referred to as the antioxidant-responsive element ( ARE). In this study, we demonstrate that Nrf2 protects neurons in mixed primary neuronal cultures containing both astrocytes (similar to 10%) and neurons (similar to 90%) through coordinate up-regulation of ARE- driven genes. Nrf2(-/-) neurons in this mixed culture system were more sensitive to mitochondrial toxin ( 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine or rotenone)-induced apoptosis compared with Nrf2(+/+) neurons. To understand the underlying mechanism of this observed differential sensitivity, we compared the gene expression profiles using oligonucleotide microarrays. Microarray data showed that Nrf2(+/+) neuronal cultures had higher expression levels of genes encoding detoxification enzymes, antioxidant proteins, calcium homeostasis proteins, growth factors, neuron-specific proteins, and signaling molecules compared with Nrf2(-/-) neuronal cultures. As predicted from the microarray data, Nrf2(-/-) neurons were indeed more vulnerable to the cytotoxic effects of ionomycin- and 2,5-di( t-butyl)-1,4-hydroquinone-induced increases in intracellular calcium. Finally, adenoviral vector-mediated overexpression of Nrf2 recovered ARE- driven gene expression in Nrf2(-/-) neuronal cultures and rescued Nrf2(+/+) neurons from rotenone- or ionomycin- induced cell death. Taken together, these findings suggest that Nrf2 plays an important role in protecting neurons from toxic insult.
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收藏
页码:37948 / 37956
页数:9
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