Role of MyD88-5 in the pathogenesis of Parkinson's disease

MyD88-5 在帕金森病发病机制中的作用

基本信息

批准号：
7848820
负责人：
Bobby Thomas
金额：
$ 36.6万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-16 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848820
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-Methyl-4-phenylpyridinium 3,4-Dihydroxyphenylacetic Acid Abbreviations Accounting Acute Affect Animal Model Apoptotic Autopsy Binding Biotin Brain Calcium Cell Death Cell Nucleus Cells Cessation of life Complex Cytosol DNA Nucleotidylexotransferase Dependovirus Development Differentiation Antigens Disease Dopamine Dopaminergic Cell Electron Transport Event Glial Fibrillary Acidic Protein Glucose Goals Homeostasis Homovanillic Acid Human ITGAM gene In Situ Nick-End Labeling In Vitro Inherited Interleukin-1 Receptors Intervention Intoxication Ions Ketoglutarate Dehydrogenase Complex Knockout Mice Knowledge LRRK2 gene Label Lewy Bodies Link MAP Kinase Gene MAPK8 gene Mediating Microtubule-Organizing Center Mitochondria Mitochondrial Proteins Mitogen-Activated Protein Kinases Modeling Molecular Monoamine Oxidase B Movement Disorders Mus Mutation MyD88 protein Myelogenous Necrosis Nerve Degeneration Neuraxis Neurons Neurotoxins Oxidases Oxygen PARK7 gene PINK1 gene PTGS2 gene Parkinson Disease Parkinsonian Disorders Pathogenesis Pathway interactions Patients Permeability Pharmaceutical Preparations Phenotype Phosphotransferases Physiological Physiology Process Protein Kinase C Proteins Recruitment Activity Reporting Resistance Reverse Transcriptase Polymerase Chain Reaction Role SAPK Scaffolding Protein Signal Pathway Signal Transduction Small Interfering RNA Stress Substantia nigra structure Testing Time Toll-like receptors Transcription Factor AP-1 Transgenes Transgenic Organisms Tyrosine 3-Monooxygenase cell injury cyclooxygenase 2 deprivation dopamine transporter dopaminergic neuron in vivo inhibitor/antagonist leucine-rich repeat kinase 2 macrophage mitochondrial dysfunction mouse model mutant new therapeutic target overexpression pars compacta public health relevance red fluorescent protein stress activated protein kinase stress-activated protein kinase 1 synuclein vesicular monoamine transporter

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by widespread neurodegeneration in the brain with profound loss of dopamine-containing neurons of the substantia nigra pars compacta. While majority of PD cases are sporadic, inherited mutations account for approximately 10% of PD cases. Existing evidence implicates a major role for stress activated protein kinases in the pathogenesis of PD. Activation of a neuronal specific c-jun N-terminal kinase-3 (JNK3), followed by recruitment to mitochondria, is associated with irreversible neurodegeneration. The mechanisms underlying this process however remain poorly understood. We have cloned a neuron-specific mitochondrial protein, called MyD88-5, which is enriched in Lewy bodies from brains of postmortem PD patients and in pathologically affected regions of the CNS in a mouse model of 1-synuclein induced PD. We showed that expression of MyD88-5 in vitro led to recruitment of JNK3 from the cytosol to mitochondria and that MyD88-5 knockout mice were resistant to dopaminergic neurodegeneration caused by parkinsonian neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). We therefore hypothesize that MyD88-5 may link JNK3 to mitochondria-dependent cell death. Three specific aims are proposed to test this hypothesis. Aim 1 will examine the role of MyD88-5 in activating JNK3 and mediating dopaminergic cell death in MPTP-induced PD using MyD88-5 knockout mice. Aim 2 will examine the role of MyD88-5 in the pathogenesis of mutant human A53T 1-synuclein-induced PD by expressing this transgene in nigral dopaminergic neurons of MyD88-5 knockout mice, or by generating and testing A53T 1- synuclein transgenic/MyD88-5-null mice. Aim 3 will dissect the role of MyD88-5 in modulating basal mitochondrial physiology and function that are important in the PD development in both MPTP- and in 1-synuclein-induced PD using MyD88-5-null mouse. Together, these studies should increase knowledge of MyD88-5-dependent cell damage pathways associated with neurodegeneration in PD and help identify new therapeutic target(s) for the treatment of PD. PUBLIC HEALTH RELEVANCE: This study propose to examine the role of a newly discovered brain mitochondrial protein, MyD88-5, in the onset and development of Parkinson's disease (PD) using the MPTP-neurotoxin and mutant human 1-synuclein mouse models. The study will enrich and refine our understanding of MyD88-5-dependent cell damage pathways observed in PD and identify new target(s) for intervention in PD pathogenesis.

描述（由申请人提供）：帕金森病（PD）是一种神经退行性运动障碍，其特征在于大脑中广泛的神经退行性变，伴有黑质致密部的含多巴胺神经元的严重丧失。虽然大多数 PD 病例是散发性的，但遗传突变约占 PD 病例的 10%。现有证据表明应激激活蛋白激酶在帕金森病的发病机制中发挥着重要作用。神经元特异性 c-jun N 末端激酶 3 (JNK3) 的激活，随后募集至线粒体，与不可逆的神经变性相关。然而，这一过程背后的机制仍然知之甚少。我们克隆了一种神经元特异性线粒体蛋白，称为 MyD88-5，该蛋白在帕金森病死后患者大脑的路易体中以及 1-突触核蛋白诱导帕金森病小鼠模型中中枢神经系统受病理影响的区域中富集。我们表明，MyD88-5 的体外表达导致 JNK3 从胞质溶胶招募到线粒体，并且 MyD88-5 敲除小鼠对帕金森神经毒素 MPTP（1-甲基-4-苯基-1,2， 3,6-四氢吡啶）。因此，我们假设 MyD88-5 可能将 JNK3 与线粒体依赖性细胞死亡联系起来。提出了三个具体目标来检验这一假设。目标 1 将使用 MyD88-5 敲除小鼠检查 MyD88-5 在 MPTP 诱导的 PD 中激活 JNK3 和介导多巴胺能细胞死亡中的作用。目标 2 将通过在 MyD88-5 敲除小鼠的黑质多巴胺能神经元中表达该转基因，或通过生成和测试 A53T 1-突触核蛋白转基因/MyD88，检查 MyD88-5 在突变型人 A53T 1-突触核蛋白诱导的 PD 发病机制中的作用-5-无效小鼠。目标 3 将剖析 MyD88-5 在调节基础线粒体生理学和功能中的作用，这对于使用 MyD88-5 缺失小鼠的 MPTP 和 1-突触核蛋白诱导的 PD 发展非常重要。总之，这些研究应增加对与 PD 神经变性相关的 MyD88-5 依赖性细胞损伤途径的了解，并有助于确定治疗 PD 的新治疗靶点。公共健康相关性：本研究旨在使用 MPTP 神经毒素和突变型人类 1-突触核蛋白小鼠模型来研究新发现的脑线粒体蛋白 MyD88-5 在帕金森病 (PD) 发病和发展中的作用。该研究将丰富和完善我们对 PD 中观察到的 MyD88-5 依赖性细胞损伤途径的理解，并确定干预 PD 发病机制的新靶点。