Oxidative damage to DNA: implications for neurodegeneration in aging

描述(申请人提供)：DNA的氧化损伤：衰老过程中神经退化的影响氧化损伤的DNA碱基8-羟基-2‘-脱氧鸟苷(Oxo8dG)在受神经元丢失影响的不同大脑区域中积累是衰老和神经疾病的常见发现。已有研究表明，在受年龄相关性神经缺陷影响的脑区，存活的神经元携带的oxo8dG水平增加；最近的研究表明，在神经元变性之前，核DNA中的oxo8dG水平显着增加。然而，oxo8dG水平升高引发神经元死亡的机制仍不清楚。我们使用了一种小鼠模型，该模型缺乏或缺失修复oxo8dG所需的酶8-羟基糖基酶Ogg1的表达。这些小鼠体内oxo8dG的积累与Ogg1的表达水平成反比，而且这种积累会随着年龄的增长而加剧。初步分析表明，缺乏Ogg1会导致黑质纹状体系统的年龄依赖性丢失，并增加对多巴胺能毒素的易感性。此外，我们还发现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附带现象，而且是神经退行性变级联中的一个参与者。这项建议中的研究旨在建立氧化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定量关系，以确定所涉及的神经退行性机制(特定目标1)。特定目标2将识别控制Ogg1表达的细胞触发因素，这将使我们能够一瞥允许oxo8dG在神经元中积累并改变细胞脆弱性的机制。特指目标3旨在验证这样一种假设，即在黑质多巴胺能神经元中重建Ogg1的表达将提供神经保护。这种黑质纹状体系统易感性增加和年龄依赖性丢失加速的模型将使我们能够测试新的药物和遗传操作来评估神经保护方法，一个基因和一个病理学的简单可以帮助我们收集导致神经元丢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生与DNA氧化损伤的增加有关；然而，与神经退行性疾病中氧化损伤导致的神经元丢失相关的机制知之甚少。这项建议旨在解决这些机制，并利用这些信息来设计针对DNA氧化损伤的治疗方法，旨在治疗或预防疾病。

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.