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Characterization of a DRD2 Variant that is Associated With a Movement Disorder

与运动障碍相关的 DRD2 变体的特征

基本信息

批准号：
10029640
负责人：
KIM Arthur NEVE
金额：
$ 34.5万
依托单位：
OREGON HEALTH & SCIENCE 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：
2020-07-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10029640
关键词：
Affect Agonist Animal Model Arrestins Behavior Binding Biological Brain Calmodulin Cell Line Cell surface Cells Characteristics Chorea Clinical Crystallization Cyclic AMP DRD2 gene Data Disease Dopamine Dopamine D2 Receptor Dopamine Receptor Dyskinetic syndrome Dystonia Electrophysiology (science)Embryo Evaluation Exhibits Exons Family Functional disorder G-Protein-Coupled Receptors GTP-Binding Proteins Generations Genes Genetic Genetic Polymorphism Goals Government Human Huntington gene Impairment Investigation Kidney Kinetics Knock-in Mouse Laboratories Link Lipid Bilayers Mental disorders Midbrain structure Modeling Motor Movement Disorders Mus Mutate Neostriatum Neurologic Dysfunctions Neurologic Symptoms Neurons Parkinson Disease Pathogenicity Persons Phenotype Property RIPK1 gene Receptor Signaling Research Schizophrenia Signal Transduction Single Nucleotide Polymorphism Slice Structure Substance abuse problem System Testing Therapeutic Variant Work desensitization dopamine system dopaminergic neuron genetic pedigree genetic variant in vivo member motor impairment mouse model mutant nervous system disorder novel protein activation protein expression receptor receptor binding receptor expression receptor function recruit societal costs therapeutic target

项目摘要

Project Summary Dopamine receptors are the primary therapeutic targets for a variety of neurological and psychiatric disorders, including schizophrenia, Parkinson's disease, and many other movement disorders. The five subtypes of dopamine receptors (D1-D5) are members of the superfamily of G protein-coupled receptors. This proposal is focused on the D2 receptor and, in particular, on the functional consequences of a novel DRD2 allelic variant that is linked to a movement disorder in at least one pedigree. The two Aims will test the hypotheses that the putatively pathogenic variant will exhibit altered signaling and cell surface expression compared to the reference D2 receptor when expressed in a neuronal cell line (Aim 1) or in dopamine neurons in mouse brain (Aim 2a), and that mice expressing the novel variant will exhibit motor impairments consistent with the human phenotype (Aim 2b). In Aim 1 we will determine if the impaired recruitment of arrestin and enhanced activation of G proteins observed when expressed in human embryonic kidney 293 cells is also characteristic of the novel variant when expressed in a neuronal cell line. In Aim 2 we will create a knock-in mouse model of homozygous and heterozygous expression of the putatively pathogenic variant. We will evaluate the functional properties of the novel variant in midbrain dopamine neurons using slice electrophysiology, and conduct analyses of behaviors that are thought to model the human clinical condition. In addition, D2 receptor expression will be quantified in midbrain and neostriatum of the knock-in mouse. The aims proposed here will quantify the effect of this novel polymorphism on the function and expression of the D2 receptor in neuronal cells and in mouse brain and should provide a biological explanation for manifestation of neurological dysfunction in humans with this variant.

项目摘要多巴胺受体是多种神经和精神疾病的主要治疗靶点，包括精神分裂症、帕金森氏症和许多其他运动障碍。五种亚型多巴胺受体（D1-D5）是G蛋白偶联受体超家族的成员。这项建议是集中在D2受体，特别是一种新的DRD 2等位基因变体的功能后果与至少一个家系中的运动障碍有关。这两个目标将测试假设，脓毒症致病性变体将表现出改变的信号传导和细胞表面表达，当在小鼠脑中的神经元细胞系（Aim 1）或多巴胺神经元中表达时， (Aim 2a），并且表达新变体的小鼠将表现出与人类一致的运动障碍。表型（Aim 2b）。在目标1中，我们将确定抑制蛋白的募集受损和激活增强是否与抑制蛋白的表达有关。当在人胚肾293细胞中表达时观察到的G蛋白的表达也是新的特征。当在神经元细胞系中表达时，其是变体。在目标2中，我们将建立一个敲入小鼠模型，以及脓疱病致病性变体的杂合表达。我们将评估的功能特性中脑多巴胺神经元的新变异，并进行分析，被认为是模拟人类临床状况的行为。此外，D2受体表达将是在敲入小鼠的中脑和新纹状体中定量。这里提出的目标将量化效果这种新的多态性对神经元细胞和小鼠中D2受体的功能和表达的影响大脑，并应提供一个生物学解释的表现，神经功能障碍的人类与这个变种。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reply to: "Childhood Onset Chorea Caused by a Recurrent De Novo DRD2 Variant".

回复：“由复发性新发 DRD2 变异引起的儿童期舞蹈病”。

DOI：
10.1002/mds.28635
发表时间：
2021
期刊：
Movement disorders : official journal of the Movement Disorder Society
影响因子：
0
作者：
vanderWeijden,MarlousCM;Rodriguez-Contreras,Dayana;Neve,KimA;Verbeek,DinekeS;Tijssen,MarinaAJ
通讯作者：
Tijssen,MarinaAJ

A Gain-of-Function Variant in Dopamine D2 Receptor and Progressive Chorea and Dystonia Phenotype.

DOI：
10.1002/mds.28385
发表时间：
2021-03
期刊：
Movement disorders : official journal of the Movement Disorder Society
影响因子：
0
作者：
van der Weijden MCM;Rodriguez-Contreras D;Delnooz CCS;Robinson BG;Condon AF;Kielhold ML;Stormezand GN;Ma KY;Dufke C;Williams JT;Neve KA;Tijssen MAJ;Verbeek DS
通讯作者：
Verbeek DS