Neuronal Dysfunction in Fragile X Tremor Ataxia Syndrome

脆性 X 震颤共济失调综合征的神经元功能障碍

基本信息

批准号：
8764626
负责人：
Peter K Todd
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-10-01 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764626
关键词：
5&apos Untranslated Regions Address Age Alzheimer&apos s Disease Animal Model Animals Behavioral Behavioral Assay Binding Brain CGG repeat CGG repeat expansion Cause of Death Clinic Clinical Clinical Trials Cognitive deficits DLG4 gene Defect Degenerative Disorder Dementia Disease Dissociation Electrophysiology (science)FMR1 FMR1 Gene FMRP FXTAS Fragile X Mental Retardation Protein Fragile X Syndrome Functional disorder Gait abnormality Genes Goals Grant Health Healthcare Hippocampus (Brain)Impaired cognition Inherited Lead Long-Term Depression Mental Retardation Messenger RNA Metabotropic Glutamate Receptors Methods Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Nucleotides Pathogenesis Patients Pharmaceutical Preparations Phase II/III Trial Phenotype Play Population Production Protein Biosynthesis Proteins RNA RNA-Binding Proteins Research Role Sampling Slice Sum Symptoms Synapses Synaptic plasticity System Techniques Testing Therapeutic Therapeutic Agents Toxic effect Transcript Translating Translations Tremor Tremor/Ataxia Syndrome Veterans Work clinical phenotype clinically relevant disability juvenile animal men mouse model new therapeutic target novel novel therapeutic intervention receptor research clinical testing research study response synaptic function therapeutic development therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Objectives: Fragile X associated Tremor Ataxia Syndrome (FXTAS) is a common inherited neurodegenerative disorder characterized by dementia, gait disorder and tremor. It results from an expanded CGG nucleotide repeat in the Fragile X Mental Retardation gene, FMR1. This repeat expansion interferes with translation of the Fragile X protein, FMRP, such that it's basal and activity-dependent expression is lower in patients and in animal models. There is emerging evidence that FMRP dysfunction may also contribute to other neurodegenerative disorders such as Alzheimer's disease. Our application addresses the critical question of whether FMRP insufficiency plays a meaningful role in FXTAS pathogenesis. To begin addressing this question, we evaluated whether neuronal dysfunction was present in a mouse model of FXTAS. We reasoned that the CGG repeat would block production of FMRP at synapses, leading to defects in synaptic plasticity that could contribute to the clinical phenotype in patients. Our preliminary results demonstrate alterations in synaptic plasticity in FXTAS model mice that mirror changes seen in mouse models of Fragile X Syndrome (FXS) that completely lack FMRP. These changes in synaptic electrophysiology are mechanistically distinct and correlate with a decrease in both basal and activity dependent expression of FMRP. These preliminary findings lead to our central hypothesis that translational inefficiency of expanded CGG repeat FMR1 mRNA contributes to neuronal dysfunction and clinical disease in FXTAS. The central objective of the proposed experiments is to define the mechanisms by which this neuronal dysfunction occurs in FXTAS model mice, with a long-term objective of developing novel therapeutic targets for Veterans with FXTAS and other neurodegenerative conditions. Research Plan/Methods: To address our central hypothesis, we will utilize a combination of molecular, cellular and electrophysiological techniques in which our labs already have established expertise. We will first determine the mechanistic features by which mGluR dependent long term depression is altered in cultured neurons and hippocampal slices from CGG-KI and FMR1 KO mice. To potentially translate these findings toward therapeutic development, we will take advantage of established work in models of FXS, where FMRP expression is completely lost. In these systems, antagonists to type I mGluRs alleviate many aspects of the phenotype seen in animal models. Phase II and III trials are ongoing in FXS with these drugs. Thus, we will test the potential efficacy of mGluR antagonists in a model of FXTAS using established behavioral assays known to be abnormal in FXTAS mice or patients. Clinical Relevance: The long term objective of this work is rational therapeutic development for patients with FXTAS and other degenerative disorders such as Alzheimer's disease where FMRP may play a role in disease pathogenesis. The proposed experiments should define an important role for FMRP dysfunction in FXTAS and potentially in other neurodegenerative disorders. These studies also provide pre-clinical testing of a promising therapeutic agent already in clinical trials, thus offering the promise of rapid clinical translation. In sum, the proposed experiments are novel, feasible and of high significance to both FXTAS and more common neurodegenerative disorders such as Alzheimer's disease

描述（由申请人提供）：目标：脆弱的X相关性共济失调综合征（FXTA）是一种以痴呆症，步态障碍和震颤为特征的常见遗传神经退行性疾病。它是由于脆弱的X智力低下基因FMR1中的CGG核苷酸重复的扩展而产生的。这种重复膨胀会干扰脆弱的X蛋白FMRP的翻译，因此它的基础和活性依赖性表达在患者和动物模型中较低。有新兴的证据表明，FMRP功能障碍也可能导致其他神经退行性疾病，例如阿尔茨海默氏病。我们的应用程序解决了FMRP功能不全是否在FXTAS发病机理中起着有意义的作用的关键问题。为了开始解决这个问题，我们评估了FXTA的小鼠模型中是否存在神经元功能障碍。我们认为，CGG重复会阻止FMRP在突触下的产生，从而导致突触可塑性缺陷，这可能有助于患者的临床表型。我们的初步结果表明，FXTAS模型小鼠突触可塑性的改变，这些镜像在脆弱X综合征（FXS）中看到的镜像变化完全缺乏FMRP。突触电生理学的这些变化在机械上是不同的，并且与FMRP的基础和活性依赖性表达的降低相关。这些初步发现导致了我们的核心假设，即扩大的CGG重复FMR1 mRNA的转化效率低效率导致FXTA中的神经元功能障碍和临床疾病。提出的实验的核心目的是定义该神经元功能障碍在FXTAS模型小鼠中发生的机制，其长期目标是为具有FXTA和其他神经退行性疾病的退伍军人开发新的治疗靶标。研究计划/方法：为了解决我们的中心假设，我们将利用分子，细胞和电生理技术的结合，其中我们的实验室已经建立了专业知识。我们将首先确定在CGG-KI和FMR1 KO小鼠的培养神经元和海马切片中改变依赖MGLUR的长期抑郁的机械特征。为了将这些发现转化为治疗发展，我们将利用FXS模型中的既定工作，在FMRP表达完全丢失。在这些系统中，对I型mglurs的拮抗剂减轻了动物模型中表现型的许多方面。这些药物在FXS中正在进行II和III期试验。因此，我们将使用已知在FXTA小鼠或患者中已知异常的行为分析来测试MGLUR拮抗剂在FXTA模型中的潜在疗效。临床相关性：这项工作的长期目标是针对FXTA和其他退行性疾病的患者（例如FMRP可能在疾病发病机理中发挥作用的阿尔茨海默氏病）的理性治疗发展。提出的实验应定义FMRP功能障碍在FXTA中的重要作用，并有可能在其他神经退行性疾病中。这些研究还提供了临床试验中已经有前途的治疗剂的临床前测试，从而提供了快速临床翻译的希望。总而言之，提出的实验是新颖，可行的，并且对FXTA和更常见的神经退行性疾病（例如阿尔茨海默氏病）具有很高的意义