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。这父母赠款的总体目标是了解功能失调的LRRK2如何触发ATM介导的DNA 损坏响应途径，会损害线粒体DNA修复能力，从而增加线粒体DNA损伤，最终促进下游致病性PD级联反应。特定于此研究补充剂，我们发现突变LRRK2的作用扩展到核DNA损伤。基于这些数据，冈萨雷斯亨特博士将确定核DNA病变的分子身份 LRRK2和特发性PD之间的共同点。她将学习新的技术专业知识和方法论，发布有影响力的研究并获得竞争性K赠款的关键初步数据，以启动独立科学职业。总的来说，该项目将直接完成父母的赠款和正在进行的实验实验室了解由LRRK2功能障碍驱动的共享途径，以便为PD提供新的见解病理生理学，因此导致了新的疗法。