Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
J Neurosci. 2012 Aug 1;32(31):10507-15. doi: 10.1523/JNEUROSCI.1494-12.2012.
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.
亚历山大病是一种致命的神经退行性疾病，由神经胶质纤维酸性蛋白（GFAP）的显性突变引起。该疾病的特征是在星形胶质细胞的细胞体和突起中存在称为 Rosenthal 纤维的蛋白包涵体，以及由转录因子 Nrf2 介导的抗氧化反应。我们试图测试在亚历山大病的小鼠模型中进一步提高 Nrf2 的水平是否有益。在 R236H GFAP 突变小鼠的星形胶质细胞中强制过表达 Nrf2，可降低所有检查的脑区（嗅球、海马体、大脑皮层、脑干、小脑和脊髓）中的 GFAP 蛋白，并降低嗅球、海马体、胼胝体和脑干中的 Rosenthal 纤维。Nrf2 的过表达还使 R236H 小鼠的体重恢复到接近野生型水平。Nrf2 调节几种参与抗氧化分子谷胱甘肽内稳态的基因，Nrf2 在其他神经疾病中的神经保护作用可能反映了谷胱甘肽恢复到正常水平。然而，R236H 小鼠的谷胱甘肽水平并没有降低。Nrf2 的过表达并未改变嗅球中的谷胱甘肽水平或氧化型谷胱甘肽与还原型谷胱甘肽的比值（表明氧化应激），而 Nrf2 可显著降低 GFAP 水平。通过敲除 GCLM（谷氨酸-半胱氨酸连接酶修饰亚基）耗尽谷胱甘肽也不会影响 R236H 小鼠的 GFAP 水平或体重。这些数据表明，Nrf2 的有益作用不是通过谷胱甘肽介导的。
