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：
10687197
负责人：
LAURIE H SANDERS
金额：
$ 45.38万
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/10687197
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 Phenotype Phosphorylation 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 neuroprotection neurotoxic novel novel therapeutic intervention pharmacologic repaired response therapeutic target toxicant trafficking

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. 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.

抽象的帕金森氏病（PD）是最常见的神经退行性运动障碍，超过一千万全世界的人们都生活在PD。迄今为止，治疗只有症状；他们不会改变不可能的疾病的进展。家庭和特发性PD的最常见原因是富含亮氨酸的突变重复激酶2（LRRK2）。 LRRK2相关和特发性PD表现出线粒体损伤，但是我们对PD线粒体功能障碍的分子基础的理解有限。在我们的努力中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相关和特发性PD的共享表型。未修复的线粒体 DNA损伤可能会产生主要的不良细胞作用，影响遗传和蛋白质不稳定性，妥协生物能功能，增加活性氧和触发细胞死亡。最近的初步研究桑德斯实验室（Sanders Lab）发现，阻断ATM的激酶活性（一种功能，具有感知，信号和信号的激酶促进DNA损伤的修复）营救了PD诱导的线粒体DNA损伤。我们进一步观察到激活ATM并启动DNA损伤响应途径。有趣的是，线粒体DNA修复特异性线粒体氧化物DNA病变的同时增加，容量会受到损害。我们的中心假设是功能失调的LRRK2触发ATM介导的DNA损伤响应途径，该途径损害线粒体DNA修复能力，导致线粒体DNA损伤的增加，最终促进下游致病性PD级联。我们将以三个特定目标来检验这一假设使用已建立的神经元和鼠PD模型的综合分子，生化和细胞技术。目的 1将确定线粒体DNA损伤的分子性质和对LRRK2激酶的依赖性活动。 AIM 2将定义细胞机制，线粒体DNA损伤在PD中积累。 AIM 3将确定ATM对PD相关表型的贡献。这个项目将推动我们的了解LRRK2在维持线粒体稳态方面的功能。此外，临床前测试可能建立ATM作为可行的治疗靶标，并为开发神经保护性PD奠定基础治疗策略。