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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：
10098948
负责人：
LAURIE H SANDERS
金额：
$ 50.89万
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/10098948
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 Pharmacology Phenotype 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 neurotoxic novel novel therapeutic intervention 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.

摘要