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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的帕金森病 (PD) 是最常见的神经退行性运动障碍，超过一千万迄今为止，全世界都有帕金森病患者，治疗只是对症治疗，并不能改变疾病的本质。家族性和特发性 PD 的最常见原因是富含亮氨酸的突变。然而，重复激酶 2 (LRRK2) 相关的和特发性 PD 表现出线粒体损伤。我们对帕金森病线粒体功能障碍的分子基础的了解是有限的。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 LRRK2 相关性和特发性线粒体 PD 的共同表型。 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，危及生命生物能量功能，增加活性氧，并引发细胞死亡。 Sanders 实验室发现，阻断 ATM 的激酶活性（一种具有感知、信号传递和信号传递功能的激酶）促进 DNA 损伤的修复）可挽救 PD 引起的线粒体 DNA 损伤。 ATM 被激活并启动 DNA 损伤反应途径，即线粒体 DNA 修复。随着特定线粒体氧化 DNA 损伤的增加，这种能力会受到损害。父母资助的总体目标是了解功能失调的 LRRK2 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，导致线粒体 DNA 损伤，最终促进下游致病性 PD 级联反应。研究补充，我们发现内源突变体 LRRK2 与激活的 ATM 相互作用，并且这种相互作用可能是由 DNA 损伤引起的，Jennifer Liu 将根据这些数据确定分子。通过这项工作，她将获得LRRK2和ATM之间的相互作用和功能关系。专业知识和方法，发表有影响力的研究，并获取 F31 奖学金的初步数据。总体而言，该项目将直接补充家长资助和实验室正在进行的实验，以了解 LRRK2 在 DNA 损伤反应和 PD 病理生理学中的作用，这可能对新疗法的开发。