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：
8305587
负责人：
Bobby Thomas
金额：
$ 31.42万
依托单位：
AUGUSTA UNIVERSITY
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305587
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（由申请人提供）：帕金森氏病（PD）是一种神经退行性运动障碍，其特征是大脑中广泛的神经变性，含有多巴胺的神经元的严重丧失了黑质nigra pars compacta。尽管大多数PD病例都是零星的，但遗传突变约占PD病例的10％。现有证据暗示了应激激活蛋白激酶在PD发病机理中的主要作用。神经元特异性C-JUN N末端激酶-3（JNK3）随后募集到线粒体的激活与不可逆的神经变性有关。然而，该过程的基础机制仍然鲜为人知。我们将神经元特异性的线粒体蛋白（称为MyD88-5）克隆，该蛋白富含来自1-突触蛋白诱导PD的小鼠模型中CNS的大脑和CNS的病理影响区域中的Lewy体。我们表明，MyD88-5在体外的表达导致JNK3从胞质醇募集到线粒体，MyD88-5敲除小鼠对帕金森尼神经毒素MPTP引起的多巴胺能神经退行性抗性具有抵抗力（1- 1-甲基-4-甲基-4-苯基1,2,3,3,6-TETRETRINE）。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。提出了三个特定目标来检验这一假设。 AIM 1将检查MyD88-5在使用MyD88-5敲除小鼠中介导JNK3和介导多巴胺能细胞死亡的PD中的作用。 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将剖析MyD88-5在使用MyD88-5-Null小鼠中，在MPTP-和1-核蛋白诱导的PD中，在调节基底线粒体生理和功能中的作用。总之，这些研究应增加与PD中与神经变性相关的MyD88-5依赖性细胞损伤途径的了解，并有助于确定新的治疗靶标的用于治疗PD。公共卫生相关性：本研究建议使用MPTP-神经毒素和突变型人类1-核蛋白小鼠模型来检查新发现的脑线粒体蛋白MyD88-5在帕金森氏病（PD）的发作中的作用。这项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，并确定用于干预PD发病机理的新靶标。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson's Disease.

DOI：
10.14336/ad.2016.0505
发表时间：
2016-12
期刊：
Aging and disease
影响因子：
7.4
作者：
Smirnova NA;Kaidery NA;Hushpulian DM;Rakhman II;Poloznikov AA;Tishkov VI;Karuppagounder SS;Gaisina IN;Pekcec A;Leyen KV;Kazakov SV;Yang L;Thomas B;Ratan RR;Gazaryan IG
通讯作者：
Gazaryan IG

Upregulation of GPR109A in Parkinson's disease.