Oxidative damage to DNA: implications for neurodegeneration in aging

DNA 氧化损伤：对衰老过程中神经退行性病变的影响

• 批准号: 8225196
• 负责人: FERNANDO CARDOZO-PELAEZ
• 金额: $ 27.18万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225196
• 关键词: 8-hydroxy-2' -deoxyguanosine; Address; Affect; Age; Age of Onset; Aging; Agreement; Alzheimer' s Disease; Apoptosis; Brain; Brain region; Cells; Cessation of life; DNA; DNA Damage; DNA Repair Enzymes; Development; Diet; Disease; Enzymes; Exhibits; Free Radicals; Gene Mutation; Genes; Genetic; Genetic Models; Glean; Health; Knock-out; Lead; Lipids; Measurement; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Neurotoxins; Nuclear; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathologic Processes; Pathology; Pathway interactions; Patients; Play; Population; Predisposition; Process; Proteins; Role; Substantia nigra structure; System; Testing; Therapeutic; Toxin; Transgenic Organisms; Wild Type Mouse; age related; base; design; dopaminergic neuron; genetic manipulation; mouse model; mutant; nervous system disorder; neuron loss; neuroprotection; nigrostriatal dopaminergic pathway; nigrostriatal pathway; nigrostriatal system; novel; oxidative DNA damage; oxidative damage; prevent; repaired; response; synuclein

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.

描述（由申请人提供）：DNA氧化损伤：对衰老神经退行性变的影响氧化损伤的DNA碱基8-羟基-2'-脱氧鸟苷（oxo8dG）在受神经元损失影响的不同脑区积累是衰老和神经系统疾病的常见发现。研究表明，受年龄相关神经功能缺陷影响的大脑区域中存活的神经元携带的oxo8dG水平增加；最近有研究表明，在神经元退化之前，核DNA中的oxo8dG水平显著增加。然而，升高的oxo8dG水平引发神经元死亡的机制尚不清楚。我们使用了一种缺乏或缺乏8-羟基糖基化酶Ogg1表达的小鼠模型，Ogg1是修复oxo8dG所必需的。这些小鼠积累的oxo8dG与Ogg1表达水平成反比，这种积累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损失，并增加对多巴胺能毒素的易感性。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的参与者。本提案的研究旨在建立氧化DNA损伤与黑质纹状体系统年龄依赖性和毒理学损失之间的定量关系，确定所涉及的神经退行性机制（Specific Aim 1）。Specific Aim 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。特异性Aim 3旨在验证在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。这种增加易感性和加速年龄依赖性损失的黑质纹状体系统模型将使我们能够测试新的药理学和遗传操作来评估神经保护方法，一种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尚不清楚。本提案旨在解决这些机制，并利用这些信息设计针对DNA氧化损伤的治疗方法，以治疗或预防疾病。