Endonuclease VIII-like 1 (NEIL1) promotes short-term spatial memory retention and protects from ischemic stroke-induced brain dysfunction and death in mice
Endonuclease VIII-like 1 (NEIL1) promotes short-term spatial memory retention and protects from ischemic stroke-induced brain dysfunction and death in mice
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DOI：
10.1073/pnas.1204156109
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发表时间：
2012-09-11
影响因子：
11.1
通讯作者：
Bohr, Vilhelm A.
中科院分区：
文献类型：
--
作者：
Canugovi, Chandrika;Yoon, Jeong Seon;Bohr, Vilhelm A.
最近的研究结果表明，神经元可以有效地修复氧化损伤的DNA，并且兴奋性谷氨酸受体的激活可以增强DNA损伤和修复。然而，在缺血性中风等病理条件下，过度的DNA损伤可引发神经元死亡。氧化性DNA损伤主要通过碱基切除修复（BER）来修复，这是一个由DNA糖基化酶启动的过程，它识别并去除受损的DNA碱基。核酸内切酶VIII样1（NEIL 1）是一种DNA糖基化酶，可识别广泛的氧化损伤。在这里，我们发现缺乏NEIL 1的小鼠在水迷宫测试中表现出记忆力受损，但在运动表现，焦虑或恐惧条件反射测试中没有异常。NEIL 1缺乏导致脑损伤增加和脑卒中局灶性缺血/再灌注模型中功能结果缺陷在缺血性脑的同侧和无压力的NEIL 1缺陷小鼠的线粒体裂解物中，含5-羟基尿嘧啶的气泡基质的切割能力较低。这些结果表明NEIL 1在学习记忆和保护神经元免受缺血损伤中起重要作用。
Recent findings suggest that neurons can efficiently repair oxidatively damaged DNA, and that both DNA damage and repair are enhanced by activation of excitatory glutamate receptors. However, in pathological conditions such as ischemic stroke, excessive DNA damage can trigger the death of neurons. Oxidative DNA damage is mainly repaired by base excision repair (BER), a process initiated by DNA glycosylases that recognize and remove damaged DNA bases. Endonuclease VIII-like 1 (NEIL1) is a DNA glycosylase that recognizes a broad range of oxidative lesions. Here, we show that mice lacking NEIL1 exhibit impaired memory retention in a water maze test, but no abnormalities in tests of motor performance, anxiety, or fear conditioning. NEIL1 deficiency results in increased brain damage and a defective functional outcome in a focal ischemia/reperfusion model of stroke. The incision capacity on a 5-hydroxyuracil-containing bubble substrate was lower in the ipsilateral side of ischemic brains and in the mitochondrial lysates of unstressed old NEIL1-deficient mice. These results indicate that NEIL1 plays an important role in learning and memory and in protection of neurons against ischemic injury.