Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52.
Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52.
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DOI：
10.1038/ncomms4496
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发表时间：
2014-03-25
影响因子：
16.6
通讯作者：
Johnson, Gail V. W.
中科院分区：
文献类型：
--
作者：
Jo, Chulman;Gundemir, Soner;Pritchard, Susanne;Jin, Youngnam N.;Rahman, Irfan;Johnson, Gail V. W.
核因子E2相关因子2（Nrf2）是一种在抗氧化应激中起关键作用的转录因子。在这里，我们提供的证据表明，Nrf2通路的激活通过诱导神经元中的自噬衔接蛋白NDP 52（也称为CALCOCO2）降低磷酸化tau的水平。NDP 52的表达，我们发现有三个抗氧化反应元件（战神）在其启动子区，强烈诱导Nrf2，其过度表达促进清除磷酸化的tau蛋白的存在下的自噬刺激剂。在Nrf2基因敲除小鼠中，磷酸化和肌氨酰不溶性tau蛋白在脑中积累，同时NDP 52水平降低。此外，NDP 52与来自阿尔茨海默病病例脑皮质样本的磷酸化tau相关，并且肌氨酰不溶性部分中磷酸化tau的量与NDP 52的量成正比。这些结果表明，NDP52在体内自噬介导的磷酸化tau降解中起关键作用。
Nuclear factor E2-related factor 2 (Nrf2) is a pivotal transcription factor in the defense against oxidative stress. Here we provide evidence that activation of the Nrf2 pathway reduces the levels of phosphorylated tau by induction of an autophagy adaptor protein NDP52 (also known as CALCOCO2) in neurons. The expression of NDP52, which we show has three antioxidant response elements (AREs) in its promoter region, is strongly induced by Nrf2, and its over-expression facilitates clearance of phosphorylated tau in the presence of an autophagy stimulator. In Nrf2 knockout mice, phosphorylated and sarkosyl-insoluble tau accumulates in the brains concurrent with decreased levels of NDP52. Moreover, NDP52 associates with phosphorylated tau from brain cortical samples of Alzheimer disease cases, and the amount of phosphorylated tau in sarkosyl-insoluble fractions is inversely proportional to that of NDP52. These results suggest that NDP52 plays a key role in autophagy-mediated degradation of phosphorylated tau in vivo.
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作者：
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影响因子：
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DOI：
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发表时间：
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影响因子：
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