DNA Damage and Repair in Parkinsons Disease

帕金森病的 DNA 损伤与修复

• 批准号: 7905370
• 负责人: LAURIE H SANDERS
• 金额: $ 5.16万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2011-10-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7905370
• 关键词: Antioxidants; Autopsy; Biochemical; Brain; DNA Damage; DNA Repair; Disease; Dopaminergic Cell; Enzymes; Event; Human; In Vitro; Investigation; Link; Metabolic; Modeling; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; OGG1 gene; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Process; Proteins; Quality of life; Reactive Oxygen Species; Role; Rotenone; Substantia nigra structure; System; Techniques; Testing; Therapeutic; age related; base; brain tissue; dopaminergic neuron; in vivo Model; member; mitochondrial genome; neuron loss; neuroprotection; novel; oxidative DNA damage; prevent; public health relevance; repaired; research study; therapy development

DESCRIPTION (provided by applicant): Neurons may be particularly prone to DNA damage by reactive oxygen species due to their high metabolic activity and low levels of antioxidant defenses [1]. Repair of oxidative DNA damage is therefore essential for normal brain function. Very little is known about neuronal DNA repair and therefore it is an important field for investigation. An etiological link to DNA damage via oxidative stress has been implicated in the pathogenesis of Parkinson's disease (PD) [2, 3]. PD is a progressive neurodegenerative disorder that is pathologically characterized largely by the loss of dopaminergic neurons of the substantia nigra. The initial underlying mechanism(s) that triggers neurodegeneration in PD is unknown. Elevated levels of DNA damage were detected in the dopaminergic neurons of the substantia nigra in PD patients [4-6]. It is unclear whether DNA damage is responsible for neuronal loss or is an epiphenomenon of the disease in the surviving neurons. Expression of "GO" enzymes (OGG1, MUTY, and MTH1), proteins involved in the repair of oxidative DNA damage, were also found to be increased in the dopaminergic neurons in the substantia nigra of PD patients [7- 9]. However, the extent to which the GO system acts to prevent DNA damage and/or mutations in both the nuclear and mitochondrial genomes in neurons is presently unclear. The proposed experiments will test the hypothesis that DNA damage is an early event in dopaminergic cell loss in the substantia nigra and that the GO pathway is important in protecting against such oxidative DNA damage. If DNA damage is potentially an underlying mechanism of neuronal degeneration, and GO repair is important in preventing this damage, these represent novel targets for the development of treatments to slow the progression of PD. A combination of molecular, biochemical and cellular techniques using rotenone models of PD and human postmortem brain tissues will be utilized. This proposal has the following two specific aims: (1) Determine the temporal and spatial role of DNA damage in the progressive loss of dopaminergic neurons; and (2) Determine the role of the GO members (OGG1, MutY, Mth1) in the repair of rotenone-induced DNA damage in both in vitro and in vivo models of PD. PUBLIC HEALTH RELEVANCE: Despite significant advances in the PD field over the last couple of decades, there are still major gaps in our understanding of the underlying mechanism(s) contributing to the progressive neurodegenerative process, and a consequent lack of effective therapeutics available to PD patients. Demonstration that nigral dopamine neuron degeneration is related to their propensity to accumulate unrepaired DNA damage could form the basis of novel therapies for neuroprotection in PD and other age-related neurodegenerative disorders. A strategy to slow the progression of PD would have a considerable positive influence on the quality of life for PD patients.

描述（由申请人提供）： 由于神经元的高代谢活性和低水平的抗氧化防御能力，神经元可能特别容易受到活性氧的 DNA 损伤 [1]。因此，氧化 DNA 损伤的修复对于正常的大脑功能至关重要。人们对神经元 DNA 修复知之甚少，因此它是一个重要的研究领域。氧化应激与 DNA 损伤的病因学联系与帕金森病 (PD) 的发病机制有关 [2, 3]。 PD是一种进行性神经退行性疾病，其病理特征主要在于黑质多巴胺能神经元的丧失。引发帕金森病神经变性的最初潜在机制尚不清楚。在 PD 患者的黑质多巴胺能神经元中检测到 DNA 损伤水平升高 [4-6]。目前尚不清楚 DNA 损伤是否是神经元损失的原因，或者是存活神经元疾病的附带现象。 “GO”酶（OGG1、M​​UTY 和 MTH1）（参与修复氧化 DNA 损伤的蛋白质）的表达也被发现在 PD 患者黑质的多巴胺能神经元中增加 [7-9]。然而，GO 系统在多大程度上可以防止神经元核基因组和线粒体基因组的 DNA 损伤和/或突变，目前尚不清楚。拟议的实验将验证以下假设：DNA 损伤是黑质多巴胺能细胞损失的早期事件，并且 GO 途径对于防止此类氧化性 DNA 损伤非常重要。如果 DNA 损伤可能是神经元变性的潜在机制，而 GO 修复对于预防这种损伤很重要，那么这些就代表了开发减缓 PD 进展的治疗方法的新靶点。将利用分子、生物化学和细胞技术的组合，使用PD和人类死后脑组织的鱼藤酮模型。该提案有以下两个具体目标：（1）确定DNA损伤在多巴胺能神经元逐渐丧失中的时间和空间作用； (2) 确定 GO 成员 (OGG1、M​​utY、Mth1) 在 PD 体外和体内模型中修复鱼藤酮诱导的 DNA 损伤中的作用。 公共卫生相关性： 尽管过去几十年来帕金森病领域取得了重大进展，但我们对进行性神经退行性过程的潜在机制的理解仍然存在重大差距，因此缺乏可供帕金森病患者使用的有效治疗方法。证明黑质多巴胺神经元变性与其累积未修复的 DNA 损伤的倾向有关，这可能为帕金森病和其他与年龄相关的神经退行性疾病的神经保护新疗法奠定基础。减缓帕金森病进展的策略将对帕金森病患者的生活质量产生相当大的积极影响。