DNA repair dysfunction in neurodegeneration

神经退行性疾病中的 DNA 修复功能障碍

• 批准号: 8148297
• 负责人: Vilhelm Bohr
• 金额: $ 19.01万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8148297
• 关键词: DNA Repair; Functional disorder; Nerve Degeneration

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.

我们研究了单个原代大鼠神经元中的DNA修复。这些神经元修复多种DNA损伤，尤其是修复紫外线诱导的DNA损伤。这一点很重要，因为紫外线对DNA的损伤是通过称为核苷酸切除修复的DNA修复过程来消除的，而核苷酸切除修复通常被认为是CNS中的缺陷。我们还发现在分化的神经元中氧化DNA损伤修复的衰减，并且我们发现在氧化应激后突触区域中的DNA修复是相当稳健的。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。具体而言，我们观察到在无毒生理水平的谷氨酸盐下，其诱导DNA损伤，并且这种损伤依赖于钙和线粒体ROS，因为钙螯合剂和线粒体抑制剂防止了DNA损伤。我们进一步表明，谷氨酸诱导的DNA损伤诱导APE 1 mRNA，APE 1是谷氨酸诱导的DNA损伤修复的关键参与者。APE 1的诱导被证明是依赖于通过钙和CREB介导的途径的信号传导。鉴于谷氨酸是最丰富的神经递质，这提出了DNA修复，记忆和学习之间存在联系的概念。