Mechanisms of mitochondrial genome integrity in familial and idiopathic Parkinson's disease

家族性和特发性帕金森病线粒体基因组完整性的机制

• 批准号: 10470384
• 负责人: LAURIE H SANDERS
• 金额: $ 45.51万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470384
• 关键词: ATM activation; ATM function; Address; Adult; Automobile Driving; Autopsy; Biochemical; Bioenergetics; Biological; Cell Death; DNA Damage; DNA Repair; DNA Sequence Alteration; DNA lesion; Data; Defect; Dependence; Development; Disease; Disease Progression; Disease model; Dose; Etiology; Exposure to; Fibroblasts; Foundations; Functional disorder; Genetic; Goals; Health; Homeostasis; Human; Idiopathic Parkinson Disease; Impairment; Investigation; Knowledge; LRRK2 gene; Link; Mediating; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Movement; Movement Disorders; Mus; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Phosphotransferases; Preclinical Testing; Proteins; Publishing; Reactive Oxygen Species; Reporting; Role; Signal Transduction; Techniques; Testing; Therapeutic; Translating; age related neurodegeneration; alpha synuclein; ataxia telangiectasia mutated protein; brain tissue; dopaminergic neuron; genome integrity; in vivo; induced pluripotent stem cell; insight; kinase inhibitor; member; mitochondrial dysfunction; mitochondrial genome; mutant; neurotoxic; novel; novel therapeutic intervention; response; therapeutic target; toxicant; trafficking

ABSTRACT Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and over ten million people worldwide are living with PD. To date, treatments are only symptomatic; they do not alter the inexorable progression of the disease. The most common cause of familial and idiopathic PD are mutations in leucine-rich repeat kinase 2 (LRRK2). LRRK2-associated and idiopathic PD demonstrate mitochondrial impairment, however our understanding of the molecular underpinnings of mitochondrial dysfunction in PD is limited. In our efforts to understand the underlying mechanisms driving mitochondrial dysfunction, we found that mitochondrial DNA damage is a shared phenotype amongst both LRRK2-associated and idiopathic PD. Unrepaired mitochondrial DNA damage can have major adverse cellular effects, impacting genetic and protein instability, compromising bioenergetic function, increasing reactive oxygen species, and triggering cell death. Recent preliminary studies by the Sanders lab has found that blocking kinase activity of ATM (a kinase that functions to sense, signal and promote repair of DNA damage) rescues PD-induced mitochondrial DNA damage. We further observed that ATM is activated and initiates the DNA damage response pathway. Interestingly, mitochondrial DNA repair capacity is impaired with a concomitant increase in specific mitochondrial oxidative DNA lesions. Our central hypothesis is that dysfunctional LRRK2 triggers the ATM-mediated DNA damage response pathway, which impairs mitochondrial DNA repair capacity, leading to an increase in mitochondrial DNA damage, ultimately promoting downstream pathogenic PD cascades. We will test this hypothesis with three specific aims that integrate molecular, biochemical and cellular techniques using established neuronal and murine PD models. Aim 1 will determine the molecular nature of the mitochondrial DNA damage and the dependency on LRRK2 kinase activity. Aim 2 will define the cellular mechanism(s) by which mitochondrial DNA damage accumulates in PD. Aim 3 will determine the contribution of ATM to PD-associated phenotypes. This project will advance our understanding of LRRK2 function in maintaining mitochondrial homeostasis. Further, preclinical testing may establish ATM as a viable therapeutic target and lay the foundation for the development of neuroprotective PD therapeutic strategies.

摘要 帕金森病(PD)是最常见的神经退行性运动障碍，超过1000万 世界各地的人都患有帕金森病。到目前为止，治疗只是有症状的；它们不能改变不可抗拒的 疾病的发展。家族性和特发性帕金森病最常见的原因是富含亮氨酸的突变 重复蛋白激酶2(LRRK2)。然而，LRRK2相关和特发性帕金森病表现为线粒体损伤 我们对帕金森病患者线粒体功能障碍的分子基础的了解有限。在我们的努力中 了解导致线粒体功能障碍的潜在机制，我们发现线粒体DNA 损伤是LRRK2相关和特发性帕金森病的共同表型。未修复的线粒体 DNA损伤可能会对细胞产生重大不利影响，影响遗传和蛋白质的不稳定性，损害 生物能量功能，增加活性氧物种，并触发细胞死亡。最近的初步研究 桑德斯实验室发现，阻断ATM(一种具有感觉、信号和信号功能的激酶)的活性 促进DNA损伤的修复)挽救PD诱导的线粒体DNA损伤。我们进一步观察到， ATM被激活，并启动DNA损伤反应途径。有趣的是，线粒体DNA修复 伴随着特定线粒体氧化DNA损伤的增加，能力受到损害。我们的中央 假说认为，功能失调的LRRK2触发了ATM介导的DNA损伤反应通路，这是 损害线粒体DNA修复能力，最终导致线粒体DNA损伤增加 促进帕金森病下游致病级联反应。我们将通过三个具体目标来检验这一假设： 使用已建立的神经元和小鼠帕金森病模型，整合分子、生化和细胞技术。目标 1将决定线粒体DNA损伤的分子性质以及对LRRK2激酶的依赖性 活动。目的2将明确线粒体DNA损伤在帕金森病中累积的细胞机制(S)。 目标3将确定ATM对帕金森病相关表型的贡献。这个项目将推进我们的 了解LRRK2在维持线粒体动态平衡中的作用。此外，临床前试验可能 建立ATM作为可行的治疗靶点，为发展神经保护性帕金森病奠定基础 治疗策略。