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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：
8109863
负责人：
Bobby Thomas
金额：
$ 36.23万
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 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8109863
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 Health Homeostasis Homovanillic Acid Human ITGAM gene In Situ Nick-End Labeling In Vitro Inherited Interleukin-1 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 N-terminal Necrosis Nerve Degeneration Neuraxis Neurons Neurotoxins Oxidases Oxygen PARK7 gene PINK1 gene PTEN 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 receptor 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(申请人提供)：帕金森病(PD)是一种神经退行性运动障碍，以脑内广泛的神经变性为特征，黑质致密部含有多巴胺的神经元严重缺失。虽然大多数帕金森病病例是散发性的，但遗传突变约占帕金森病病例的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起重要作用。神经元特异性c-jun氨基末端激酶-3(JNK3)的激活，随后重新聚集到线粒体，与不可逆转的神经退行性变有关。然而，这一进程背后的机制仍然知之甚少。我们已经克隆了一种神经元特异性线粒体蛋白MyD88-5，它富含死后帕金森病患者大脑中的路易体，以及1-突触核蛋白诱导的帕金森病小鼠模型中受影响的中枢神经系统区域。我们发现，MyD88-5的体外表达导致JNK3从胞浆重新聚集到线粒体，并且MyD88-5基因敲除小鼠对帕金森神经毒素MPTP(1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine).引起的多巴胺能神经退行性变具有抵抗力因此，我们假设MyD88-5可能将JNK3与线粒体依赖的细胞死亡联系起来。为了检验这一假说，本文提出了三个具体目标。目的1利用MyD88-5基因敲除小鼠，研究MyD88-5在MPTP诱导的帕金森病模型中激活JNK3和介导多巴胺能细胞死亡中的作用。目的通过在MYD88-5基因敲除小鼠的黑质多巴胺能神经元中表达MYD88-5基因，或通过构建和检测A53T 1-突触核蛋白转基因/MyD88-5缺失小鼠，探讨MYD88-5在突变型人A53T 1-突触核蛋白诱导的帕金森病发病机制中的作用。目的3利用MyD88-5基因缺失小鼠，分析MyD88-5在调节线粒体基础生理和功能中的作用，这些生理和功能在MPTP和1-突触核蛋白诱导的帕金森病小鼠的帕金森病发生过程中都是重要的。总之，这些研究将增加对与帕金森病神经变性相关的MyD88-5依赖的细胞损伤通路的了解，并有助于确定治疗帕金森病的新治疗靶点(S)。公共卫生相关性：这项研究建议使用MPTP神经毒素和突变的人类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)的发生和发展中的作用。本研究将丰富和完善我们对PD中MyD88-5依赖的细胞损伤通路的认识，并为PD发病机制的干预寻找新的靶点(S)。