It is unknown whether DNA damage accumulation is an upstream instigator or secondary effect of the cell death process in different populations of adult postmitotic neurons in the central nervous system. In two different mouse models of injury-induced neurodegeneration characterized by relatively synchronous accumulation of mitochondria, oxidative stress, and DNA damage prior to neuronal apoptosis, we enforced the expression of human 8-oxoguanine DNA glycosylase (hOGG1) and human apurinic-apyrimidinic endonuclease-1/Ref1 (hAPE) using recombinant adenoviruses (Ad). Thalamic lateral geniculate neurons and lumbar spinal cord motor neurons were transduced by Ad-hOGG1 and Ad-hAPE injections into the occipital cortex and skeletal muscle, respectively, prior to their target deprivation- and axotomy-induced retrograde apoptosis. Enforced expression of hOGG1 and hAPE in thalamus and spinal cord was confirmed by western blotting and immunohistochemistry. In injured populations of neurons in thalamus and spinal cord, a DNA damage response (DDR) was registered, as shown by localization of phospho-activated p53, Rad17, and replication protein A-32 immunoreactivities, and this DDR was attenuated more effectively by enforced hAPE expression than by hOGG1 expression. Enforced expression of hOGG1 and hAPE significantly protected thalamic neurons and motor neurons from retrograde apoptosis induced by target deprivation and axotomy. We conclude that a DDR response is engaged pre-apoptotically in different types of injured mature CNS neurons and that DNA repair enzymes can regulate the survival of retrogradely dying neurons, suggesting that DNA damage and activation of DDR are upstream mechanisms for this form of adult neurodegeneration in vivo, thus identifying DNA repair as a therapeutic target for neuroprotection.

中文翻译：

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强制的DNA修复酶可在神经退行性小鼠模型中挽救神经元，使其免受靶标剥夺和轴突切开术诱导的细胞凋亡。

在中枢神经系统中成年有丝分裂后神经元的不同群体中，DNA损伤累积是细胞死亡过程的上游诱因还是细胞死亡过程的继发效应尚不清楚。在特征为线粒体相对同步积累，氧化应激和神经元凋亡之前的DNA损伤的损伤诱导的神经变性的两种不同小鼠模型中，我们增强了人8-氧鸟嘌呤DNA糖基化酶（hOGG1）和人嘌呤-嘧啶核苷内切核酸酶- 1 / Ref1（hAPE），使用重组腺病毒（Ad）。丘脑外侧膝状神经元和腰脊髓运动神经元分别通过Ad-hOGG1和Ad-hAPE注射转导到枕叶皮层和骨骼肌中，然后靶剥夺和轴突切开所引起的逆行凋亡。Western blotting和免疫组织化学证实了hOGG1和hAPE在丘脑和脊髓中的表达增强。在受损的丘脑和脊髓神经元群体中，记录了DNA损伤反应（DDR），如磷酸激活的p53，Rad17和复制蛋白A-32免疫反应的定位所显示，并且通过强制执行，该DDR可以更有效地减弱hAPE的表达要比hOGG1的表达高。hOGG1和hAPE的表达增强可保护丘脑神经元和运动神经元免受靶标剥夺和轴突切开术引起的逆行凋亡。我们得出的结论是，DDR反应在不同类型的成熟CNS受损神经元中发生凋亡前过程，而DNA修复酶可以调节逆行死亡的神经元的存活，