Oxidative damage to DNA: implications for neurodegeneration in aging

描述（由申请人提供）：对DNA的氧化损伤：对衰老中神经变性的影响在受神经元损失折磨的不同脑区域中氧化损伤的DNA碱基8-羟基-2'-脱氧鸟苷（oxo8dG）的积累是衰老和神经疾病中的常见发现。已经表明，在受年龄相关的神经功能缺损影响的脑区域中存活的神经元携带增加的oxo8dG水平;最近已经证明，在神经元变性之前，核DNA中的oxo8dG水平显著增加。然而，由升高的oxo8dG水平触发的神经元死亡的机制仍然未知。我们使用了一种小鼠模型，该模型缺乏或不表达修复oxo8dG所需的酶8-羟糖基化酶Ogg1。这些小鼠积累oxo8dG的Ogg1的表达水平成反比，这种积累加剧了老化。初步分析表明，缺乏Ogg 1导致黑质纹状体系统的年龄依赖性损失和对多巴胺能毒素的敏感性增加。此外，我们发现Ogg1的表达似乎依赖于细胞氧化还原状态的变化。因此，我们假设oxo8dG水平不仅是神经退行性变的副现象，而且是神经退行性级联反应中的一个参与者。本提案中的研究旨在建立氧化性DNA损伤与黑质纹状体系统的年龄依赖性和毒理学损失之间的量子关系，确定相关的神经退行性机制（具体目标1）。具体目标2将识别控制Ogg1表达的细胞触发器，这将使我们能够瞥见允许oxo8dG在神经元中积累并改变细胞脆弱性的机制。具体目标3旨在检验黑质多巴胺能神经元中重建Ogg1表达将提供神经保护的假设。黑质纹状体系统中易感性增加和年龄依赖性损失加速的模型将使我们能够测试新的药理学和遗传操作以评估神经保护方法，一个基因一种病理的简单性可以帮助我们收集导致神经元损失的直接机制和相关的治疗意义。公共卫生相关性：大多数神经退行性疾病的发展与DNA氧化损伤增加有关;然而，与神经退行性疾病中氧化损伤驱动的神经元损失相关的机制知之甚少。该提案旨在解决这些机制，并使用这些信息来设计旨在治疗或预防疾病的靶向DNA氧化损伤的治疗方法。

DESCRIPTION (provided by applicant): Oxidative damage to DNA: implications for neurodegeneration in aging Accumulation of the oxidatively damaged DNA base 8-hydroxy-2'-deoxyguanosine (oxo8dG) in distinct brain regions afflicted by neuronal loss is a common finding in aging and neurological disease. It has been shown that surviving neurons in brain regions impacted in age-related neurological deficits carry increased levels of oxo8dG; and recently it has been demonstrated that prior to neuronal degeneration there is a significant increase in oxo8dG levels in nuclear DNA. However, the mechanism of neuronal death triggered by elevated oxo8dG levels remains unknown. We have used a mice model that is deficient or null for the expression of the enzyme 8-hydroxyglycosylase, Ogg1, required for the repair of oxo8dG. These mice accumulate oxo8dG in an inverse relation to the level of Ogg1 expression and such an accumulation is accentuated by aging. Initial analyses show that lack of Ogg1 leads to an age-dependent loss in the nigrostriatal system and an increased susceptibility to dopaminergic toxins. In addition, we have found that Ogg1 expression appears to be dependent to changes in the redox state of the cell. Thus, we hypothesize that oxo8dG levels are not only epiphenomena of neurodegeneration, but a player in the neurodegenerative cascade. The studies in this proposal are aimed to establish a quantal relation between oxidative DNA damage and age-dependent and toxicological loss of the nigrostriatal system identifying the neurodegenerative mechanism involved (Specific Aim 1). Specific Aim 2 will discern the cellular triggers that control Ogg1 expression, which will allow us to glimpse mechanism that allow for accumulation of oxo8dG in neurons and alter cell vulnerability. Specific Aim 3 is designed to test the hypothesis that reestablishing Ogg1 expression in nigral dopaminergic neurons will afford neuroprotection. This model of increased susceptibility and accelerated age-dependent loss in the nigrostriatal system will allow us to test novel pharmacological and genetic manipulations to evaluate neuroprotective approaches, the simplicity of one gene one pathology can help us glean into direct mechanisms leading to neuronal loss and relevant therapeutic implications. PUBLIC HEALTH RELEVANCE: The development of most neurodegenerative diseases is associated with increased oxidative damage to DNA; however, the mechanisms associated with oxidative damage-driven neuronal loss in neurodegenerative diseases is poorly understood. This proposal is designed to address such mechanisms and to use this information to design therapeutic approaches that target oxidative damage to DNA aimed to treat or prevent disease.