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：
10353124
负责人：
LAURIE H SANDERS
金额：
$ 2.9万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10353124
关键词：
ATM Signaling Pathway ATM activation Address Adult Affect Alkalies Alkaline Single-Cell Gel Electrophoresis Assay Anatomy Animals Automobile Driving Bioenergetics Biological Biological Assay Biology Brain Brain region C-terminal Caenorhabditis elegans Cell Culture Techniques Cell Cycle Cell Death Cell Nucleus Cells Comet Assay Complement Confocal Microscopy DNA DNA Damage DNA Double Strand Break DNA Repair DNA lesion DNA strand break Data Defect Disease Disease Progression Disease model Dissection Dose Double Strand Break Repair Etiology Fellowship Foundations Functional disorder Genetic Genome Genomic Instability Goals Grant Histones Homeostasis Human Idiopathic Parkinson Disease Immunohistochemistry Impairment LRRK2 gene Laboratories Lead Learning Mammalian Cell Measures Mediating Mentors Mentorship Methodology Methods Microtome - medical device Mitochondria Mitochondrial DNA Molecular Movement Movement Disorders Mutation Names Nerve Degeneration Neurodegenerative Disorders Nuclear Parkinson Disease Pathogenicity Pathology Pathway interactions Patients Phenotype Phosphorylation Phosphotransferases Proteins Publications Publishing Reactive Oxygen Species Reporting Research Rodent Model Role Signal Transduction Site Substantia nigra structure TP53 gene Technical Expertise Techniques Testing United States Variant base career dopaminergic neuron experience experimental study genome integrity in vivo induced pluripotent stem cell insight kinase inhibitor laboratory experience member mitochondrial dysfunction mitochondrial genome mutant neurotoxic novel novel therapeutic intervention novel therapeutics nucleic acid metabolism p53-binding protein 1 parent grant recruit response skills 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 the role of mutant LRRK2 extends to nuclear DNA damage. Based on this data, Dr. Gonzalez-Hunt will determine the molecular identity of the nuclear DNA lesions that are in common between LRRK2 and idiopathic PD. She will learn new technical expertise and methodology, publish impactful research and obtain the key preliminary data for competitive K grants to launch an independent scientific career. Overall this project will directly complement the parental grant and ongoing experiments in the lab to understand shared pathways driven by LRRK2 dysfunction, in order to provide new insights into PD pathophysiology and consequently lead to 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，我们发现突变体 LRRK2 的作用延伸至核 DNA 损伤。根据这些数据，Gonzalez-Hunt 博士将确定核 DNA 损伤的分子身份，这些损伤是她将学习新的技术专业知识和方法，并发表论文。有影响力的研究并获得竞争性 K 赠款的关键初步数据，以启动独立的总体而言，该项目将直接补充父母的资助和正在进行的实验。实验室了解 LRRK2 功能障碍驱动的共享通路，以便为 PD 提供新的见解病理生理学，从而导致新的疗法。