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: 10622266
• 负责人: LAURIE H SANDERS
• 金额: $ 8.11万
• 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/10622266
• 关键词: Address; Adult; Affect; Antigen-Antibody Complex; Automobile Driving; Binding; Biochemical; Biochemistry; Bioenergetics; Biological; Biological Assay; Cell Culture Techniques; Cell Death; Cells; Clinical Research; Committee Members; Complement; Complex; Confocal Microscopy; DNA Damage; DNA Repair; DNA analysis; DNA lesion; DNA-dependent protein kinase; Data; Development; Development Plans; Disease; Disease Progression; Etiology; Exposure to; Fellowship; Foundations; Functional disorder; Future; Genetic; Genome; Goals; Grant; Idiopathic Parkinson Disease; Immunofluorescence Immunologic; Immunoprecipitation; Impairment; Knowledge; LRRK2 gene; Laboratories; Lead; Learning; Ligation; Link; Maintenance; Mammalian Cell; Mediating; Mentors; Mentorship; Methodology; Methods; Mitochondria; Mitochondrial DNA; Molecular; Molecular Biology; Movement; Movement Disorders; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Oncology; Parkinson Disease; Pathogenicity; Pathway interactions; Persons; Phenotype; Phosphorylation; Phosphotransferases; Protein Biochemistry; Protein Overexpression; Proteins; Publications; Publishing; Reactive Oxygen Species; Regulation; Reporting; Research; Robin bird; Role; Signal Transduction; Site; Specificity; Stress; TP53 gene; Technical Expertise; Techniques; Testing; Western Blotting; Work; Yeasts; base; career; career development; cell type; experimental study; genome integrity; insight; mitochondrial dysfunction; mitochondrial genome; mouse model; mutant; neurotoxic; novel; novel therapeutic intervention; novel therapeutics; parent grant; phosphoproteomics; protein protein interaction; response; skills; toxicant; training opportunity

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. The overarching goal of the parental grant to understand how 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. Specific to this research supplement, we have discovered that endogenous mutant LRRK2 interacts with activated ATM, and this interaction may be induced by DNA damage. Based on this data, Jennifer Liu will determine the molecular interactions and functional relationship between LRRK2 and ATM. Through this work, she will gain new technical expertise and methodology, publish impactful research, and obtain preliminary data for an F31 fellowship. Overall, this project will directly complement the parental grant and ongoing experiments in the lab to understand LRRK2‘s role in the DNA damage response and PD pathophysiology, which may have implications for the development of new therapies.

摘要 帕金森病（PD）是最常见的神经退行性运动障碍， 全世界的人都患有PD。到目前为止，治疗只是治标不治本;它们不能改变不可改变的事实。 疾病的进展。家族性和特发性PD最常见的原因是富含亮氨酸的 重复激酶2（LRRK 2）。然而，LRRK 2相关和特发性PD显示线粒体损伤， 我们对PD中线粒体功能障碍的分子基础的理解是有限的。在我们努力 了解驱动线粒体功能障碍的潜在机制，我们发现线粒体DNA 损伤是LRRK 2相关和特发性PD之间共有的表型。未修复线粒体 DNA损伤可具有主要的不利细胞效应，影响遗传和蛋白质不稳定性，损害 生物能量功能，增加活性氧，并引发细胞死亡。最近的初步研究 Sanders实验室的研究发现，阻断ATM的激酶活性（一种负责感知、信号和 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 能力受损，伴随着特异性线粒体氧化DNA损伤的增加。的 父母补助金的首要目标是了解功能失调的LRRK 2如何触发ATM介导的DNA 损伤反应途径，损害线粒体DNA修复能力，导致增加 线粒体DNA损伤，最终促进下游致病性PD级联。特定于此 研究补充，我们发现内源性突变体LRRK 2与激活的ATM相互作用， 这种相互作用可能由DNA损伤引起。根据这些数据，Jennifer Liu将确定 LRRK 2和ATM之间的相互作用和功能关系。通过这项工作，她将获得新的技术 专业知识和方法，发表有影响力的研究，并获得F31奖学金的初步数据。 总的来说，这个项目将直接补充父母的赠款和正在进行的实验室实验，以了解 LRRK 2在DNA损伤反应和PD病理生理学中的作用，这可能对帕金森病的发病机制有影响。 开发新的疗法。