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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：
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）：帕金森病（PD）是一种神经退行性运动障碍，其特征为大脑中广泛的神经退行性病变，伴有黑质背侧部含多巴胺神经元的严重缺失。虽然大多数PD病例是散发性的，但遗传性突变占PD病例的约10%。现有的证据表明，应激活化蛋白激酶在PD的发病机制中起着重要作用。神经元特异性c-jun N-末端激酶-3（JNK 3）的激活，随后募集到线粒体，与不可逆的神经变性相关。然而，这一过程的机制仍然知之甚少。我们已经克隆了一个神经元特异性的线粒体蛋白，称为MyD 88 -5，这是丰富的路易体从死后PD患者的大脑和在1-突触核蛋白诱导的PD的小鼠模型中的CNS的病理受影响的地区。我们发现，MyD 88 -5在体外的表达导致JNK 3从胞质溶胶募集到线粒体，并且MyD 88 -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）引起的多巴胺能神经变性具有抗性。因此，我们假设MyD 88 -5可能将JNK 3与细胞凋亡相关。提出了三个具体目标来检验这一假设。目的1：利用MyD 88 - 5基因敲除小鼠研究MyD 88 -5在MPTP诱导的PD中激活JNK 3和介导多巴胺能细胞死亡的作用。目的2将通过在MyD 88 -5敲除小鼠的黑质多巴胺能神经元中表达该转基因，或通过产生和测试A53 T1-突触核蛋白转基因/MyD 88 -5-null小鼠来检查MyD 88 -5在突变型人A53 T1-突触核蛋白诱导的PD的发病机制中的作用。目的3将使用MyD 88 -5缺失小鼠剖析MyD 88 -5在调节基础线粒体生理和功能中的作用，所述基础线粒体生理和功能在MPTP和1-突触核蛋白诱导的PD中的PD发展中是重要的。总之，这些研究应该增加对与PD神经退行性变相关的MyD 88 -5依赖性细胞损伤途径的了解，并帮助确定治疗PD的新治疗靶点。公共卫生相关性：本研究拟采用MPTP神经毒素和突变型人1-突触核蛋白小鼠模型，研究新发现的脑线粒体蛋白MyD 88 -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MyD 88 -5依赖性细胞损伤途径的理解，并确定PD发病机制干预的新靶点。

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.