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）： 由于其高代谢活性和低水平的抗氧化剂防御能力，神经元可能特别容易受反应性氧的DNA损伤[1]。因此，修复氧化DNA损伤对于正常的脑功能至关重要。关于神经元DNA修复知之甚少，因此它是研究的重要领域。通过氧化应激与DNA损伤的病因关系已与帕金森氏病（PD）的发病机理有关[2，3]。 PD是一种进行性神经退行性疾病，在很大程度上是由斑nigra的多巴胺能神经元丧失的病理学来表征的。触发PD神经退行性的初始基本机制尚不清楚。在PD患者中，在底底尼格拉的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损伤是导致神经元丧失的原因还是幸存神经元中该疾病的epiphenomenon。在PD患者的黑质中，在多巴胺能神经元中，还发现参与氧化DNA损伤的蛋白质的“ GO”酶（OGG1，MUTY和MTH1），涉及氧化DNA损伤的蛋白质[7-9]。但是，目前尚不清楚GO系统在核和线粒体基因组中的DNA损伤和/或突变的影响程度尚不清楚。提出的实验将检验以下假设：DNA损伤是黑质中多巴胺能细胞损失的早期事件，而GO途径对于防止这种氧化DNA损伤很重要。如果DNA损伤可能是神经元变性的潜在机制，并且GO修复对于防止这种损害很重要，则这些代表了开发治疗以减慢PD进展的新目标。将利用使用PD的烤面包酮模型和人类后脑组织的分子，生化和细胞技术的结合。该提案具有以下两个特定目的：（1）确定DNA损伤在多巴胺能神经元进行性丧失中的时间和空间作用； （2）确定GO成员（OGG1，MUTY，MTH1）在紫红酮诱导的DNA损伤的PD模型中的作用。 公共卫生相关性： 尽管在过去的几十年中，PD领域取得了重大进展，但我们对促进性神经退行性过程的潜在机制的理解仍然存在很大的差距，因此缺乏PD患者可用的有效治疗剂。证明了ni虫多巴胺神经元变性与它们积累未经修复的DNA损伤的倾向有关，这可能构成了PD和其他与年龄相关的神经退行性疾病的新型神经保护疗法的基础。减慢PD进展的策略将对PD患者的生活质量产生相当大的积极影响。