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Metabolic Dysregulation in FXTAS Pathogenesis

FXTAS 发病机制中的代谢失调

基本信息

批准号：
10224940
负责人：
Emily Graves Allen
金额：
$ 19.77万
依托单位：
EMORY 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：
2020-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224940
关键词：
Adult Affect Age Alleles Alzheimer&apos s Disease Animal Model Autopsy Binding Proteins Biochemical Biological Markers Brain Cell model Cell physiology Central Nervous System Diseases Cerebellum Data Disease Dropout Drosophila genus Drug Targeting Enzymes Exhibits FMR1 FXTAS Gait Ataxia Genes Genetic Screening Genetic study Homo Human Huntington Disease Impaired cognition Individual Intention Tremor Investigation Longitudinal cohort study Mediating Messenger RNA Metabolic Metabolic Pathway Metabolism Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Inclusion Parkinson Disease Parkinsonian Disorders Pathogenesis Pathway interactions Patients Phenotype Plasma Production Proteins RNA Role Sampling Sphingolipids Symptoms Testing Therapeutic Effect Toxic effect Translations Triplet Multiple Birth Ubiquitin Work biomarker identification brain tissue cohort disease diagnosis fly gain of function glucosylceramidase lipidomics men metabolomics mouse model mutant polypeptide small molecule therapeutic development therapeutic target

项目摘要

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers of premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Common features of FXTAS include progressive intention tremor, gait ataxia, Parkinsonism, and cognitive decline. The neuropathological hallmarks of FXTAS include ubiquitin-positive intranuclear inclusions throughout the brain and marked dropout of Purkinje neurons in the cerebellum. Currently, data support two non-mutually exclusive molecular pathogenesis mechanisms for FXTAS: 1) RNA gain-of-function, in which rCGG repeat- binding proteins (RBPs) become functionally limited through sequestration by lengthy rCGG repeats, and 2) Repeat-associated non-AUG (RAN) translation, whereby translation through the CGG (or antisense CCG) repeats leads to the production of toxic homo-polypeptides, such as FMRpolyG, which in turn interfere with a variety of cellular functions. Multiple mouse models have been developed to study these mechanisms. Much remains unknown regarding the metabolic alterations associated with FXTAS, especially in the brain, and the most affected region, the cerebellum. Our previous work identified the metabolic alterations associated with FXTAS pathogenesis using our FXTAS mouse model that expresses 90 CGG repeats in cerebellar Purkinje neurons and exhibits the key phenotypic features of FXTAS. By combining global metabolic profiling with a Drosophila genetic screen, we have found that the sphingolipid metabolic pathway can modulate rCGG repeat toxicity. A preliminary study of 5 FXTAS postmortem brains compared to age-matched controls also identified alterations in the sphingolipid pathway. Untargeted metabolomic analysis of plasma samples from men with symptoms of FXTAS identified significant alterations in the sphingolipid pathway compared to noncarrier men. In the proposed study, we will expand on these findings using additional FXTAS mouse models, Drosophila models, and human samples. First, we will compare the lipidomic profile of a mouse model that expresses 99 CGG repeats and the FMRpolyG protein to a mouse model that expresses the expanded repeat without expressing the FMRpolyG protein. In addition, we will test for amelioration of FXTAS pathogenesis in flies with a drug that targets β-glucocerebrosidase (GBA), a key enzyme in the sphingolipid pathway that we have found is able to modulate rCGG repeat toxicity. We will also investigate the profile in FXTAS patients using additional post mortem brain samples and plasma samples that have been collected on a longitudinally-studied cohort for FXTAS pathogenesis. Our proposed work investigating the metabolic changes in FXTAS will aid in the identification of biomarkers as well as in understanding the pathogenesis of disease

脆性 X 相关震颤/共济失调综合征 (FXTAS) 是一种成人发病的神经退行性疾病，影响脆性 X 智力低下 1 (FMR1) 基因的前突变等位基因（55-200 个 CGG 重复）的携带者。 FXTAS 的常见特征包括进行性意向性震颤、步态共济失调、帕金森症和认知障碍衰退。 FXTAS 的神经病理学特征包括遍及整个细胞的泛素阳性核内包涵体大脑和小脑中浦肯野神经元明显缺失。目前数据支持两种非互 FXTAS 独有的分子发病机制：1) RNA 功能获得，其中 rCGG 重复结合蛋白 (RBP) 通过较长的 rCGG 重复隔离而受到功能限制，2) 重复相关的非 AUG (RAN) 翻译，即通过 CGG（或反义 CCG）进行翻译重复序列会导致有毒同源多肽的产生，例如 FMRpolyG，这反过来会干扰多种细胞功能。已经开发了多种小鼠模型来研究这些机制。很多关于与 FXTAS 相关的代谢改变（尤其是在大脑中）和受影响最严重的区域，小脑。我们之前的工作确定了与使用我们的 FXTAS 小鼠模型研究 FXTAS 发病机制，该模型在小脑浦肯野细胞中表达 90 个 CGG 重复序列神经元并表现出 FXTAS 的关键表型特征。通过将全球代谢分析与果蝇基因筛选，我们发现鞘脂代谢途径可以调节rCGG重复毒性。对 5 个 FXTAS 死后大脑与年龄匹配的对照进行比较的初步研究还发现鞘脂途径的改变。对患有以下疾病的男性血浆样本进行非靶向代谢组学分析与非携带者男性相比，FXTAS 的症状表明鞘脂通路存在显着改变。在拟议的研究中，我们将使用其他 FXTAS 小鼠模型（果蝇）来扩展这些发现模型和人体样本。首先，我们将比较表达 99 的小鼠模型的脂质组学特征 CGG 重复序列和 FMRpolyG 蛋白用于表达扩展重复序列的小鼠模型，无需表达 FMRpolyG 蛋白。此外，我们将测试果蝇 FXTAS 发病机制的改善情况一种针对 β-葡萄糖脑苷脂酶 (GBA) 的药物，β-葡萄糖脑苷脂酶是我们发现的鞘脂途径中的关键酶能够调节 rCGG 重复毒性。我们还将使用额外的方法来调查 FXTAS 患者的概况在纵向研究队列中收集的死后脑样本和血浆样本 FXTAS发病机制。我们提出的研究 FXTAS 代谢变化的工作将有助于识别生物标志物以及了解疾病的发病机制