Beneficial Effects of Nrf2 Overexpression in a Mouse Model of Alexander Disease
Beneficial Effects of Nrf2 Overexpression in a Mouse Model of Alexander Disease
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DOI：
10.1523/jneurosci.1494-12.2012
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发表时间：
2012-08-01
影响因子：
5.3
通讯作者：
Messing, Albee
中科院分区：
文献类型：
--
作者：
Daniels, Christine M. LaPash;Austin, Elizabeth V.;Messing, Albee
亚历山大病是一种由胶质细胞酸性蛋白（GFAP）显性突变引起的致命性神经退行性疾病。该疾病的特征在于星形胶质细胞细胞体和过程中的称为罗森塔尔纤维的蛋白质内含物，以及由转录因子Nrf 2介导的抗氧化反应。我们试图在亚历山大病的小鼠模型中测试Nrf 2的进一步升高是否有益。在R236 H GFAP突变小鼠的星形胶质细胞中强制Nrf 2过表达降低了所有脑区（嗅球、海马、大脑皮质、脑干、小脑和脊髓）中的GFAP蛋白，并降低了嗅球、海马、胼胝体和脑干中的罗森塔尔纤维。Nrf 2过表达也使R236 H小鼠的体重恢复到接近野生型水平。Nrf 2调节参与抗氧化分子谷胱甘肽体内平衡的几个基因，Nrf 2在其他神经系统疾病中的神经保护作用可能反映谷胱甘肽恢复到正常水平。然而，R236 H小鼠的谷胱甘肽水平没有降低。Nrf 2过表达没有改变嗅球中的谷胱甘肽水平或还原型谷胱甘肽与氧化型谷胱甘肽的比率（指示氧化应激），其中Nrf 2显著降低GFAP。通过敲除GCLM（谷氨酸-半胱氨酸连接酶修饰亚基）耗尽谷胱甘肽也不影响R236 H小鼠的GFAP水平或体重。这些数据表明Nrf 2的有益作用不是通过谷胱甘肽介导的。
Alexander disease is a fatal neurodegenerative disease caused by dominant mutations in glial fibrillary acidic protein (GFAP). The disease is characterized by protein inclusions called Rosenthal fibers within astrocyte cell bodies and processes, and an antioxidant response mediated by the transcription factor Nrf2. We sought to test whether further elevation of Nrf2 would be beneficial in a mouse model of Alexander disease. Forcing overexpression of Nrf2 in astrocytes of R236H GFAP mutant mice decreased GFAP protein in all brain regions examined (olfactory bulb, hippocampus, cerebral cortex, brainstem, cerebellum, and spinal cord) and decreased Rosenthal fibers in olfactory bulb, hippocampus, corpus callosum, and brainstem. Nrf2 overexpression also restored body weights of R236H mice to near wild-type levels. Nrf2 regulates several genes involved in homeostasis of the antioxidant molecule glutathione, and the neuroprotective effects of Nrf2 in other neurological disorders may reflect restoration of glutathione to normal levels. However, glutathione levels in R236H mice were not decreased. Nrf2 overexpression did not change glutathione levels or ratio of reduced to oxidized glutathione (indicative of oxidative stress) in olfactory bulb, where Nrf2 dramatically reduced GFAP. Depletion of glutathione through knock-out of the GCLM (glutamate-cysteine ligase modifier subunit) also did not affect GFAP levels or body weight of R236H mice. These data suggest that the beneficial effects of Nrf2 are not mediated through glutathione.