DNA repair dysfunction in neurodegeneration

我们研究了单个大鼠初级神经元的DNA修复。这些神经元可以修复多种DNA损伤，其中修复紫外线诱导的DNA损伤是一项特别新颖的研究。这一点很重要，因为紫外线对DNA的损伤是通过DNA修复过程（称为核苷酸切除修复）来消除的，而这种修复过程通常被认为是中枢神经系统的缺陷。我们还发现分化神经元氧化DNA损伤修复的衰减，我们发现突触区域的DNA修复在氧化应激后相当强劲。此外，神经传递和DNA修复之间似乎存在联系，因为向神经元添加神经递质会增加DNA损伤和修复。具体来说，我们观察到，在无毒生理水平的谷氨酸，它诱导DNA损伤，这种损伤依赖于钙和线粒体活性氧，因为钙螯合剂和线粒体抑制剂阻止DNA损伤。我们进一步发现，谷氨酸诱导的DNA损伤诱导了APE1 mRNA，并且APE1在谷氨酸诱导的DNA损伤修复中起关键作用。研究表明，APE1的诱导依赖于钙和creb介导的信号通路。鉴于谷氨酸是最丰富的神经递质，这就提出了DNA修复、记忆和学习之间存在联系的概念。

We have studied DNA repair in individual primary rat neurons. These neurons repair many kinds of DNA damage, and it is particularly novel that they repair UV induced DNA damage. This is important because UV damage to DNA is removed by the DNA repair process called nucleotide excision repair, which is generally thought to be deficient in the CNS. We also find attenuation of oxidative DNA damage repair in differentiating neurons and we find that the DNA repair in the synaptic region is quite robust after oxidative stress. Furthermore, there seems to be a connection between neurotransmission and DNA repair because the addition of neurotransmitters to neurons increases DNA damage and repair. Specifically, we observed that at non-toxic physiological levels of glutamate, it induced DNA damage and this damage was dependent upon calcium and mitochondrial ROS because calcium chelators and mitochondrial inhibitors prevented the DNA damage. We further showed that the glutamate-induced DNA damage induced APE1 mRNA and that APE1 is a key player in the repair of glutamate-induced DNA damage. The APE1 induction was shown to be dependent on signaling through a calcium and CREB-mediated pathway. Given that glutamate is the most abundant neurotransmitter, this raises the notion that there exists a connection between DNA repair, memory and learning.