Metabolic Dysregulation in FXTAS Pathogenesis

FXTAS 发病机制中的代谢失调

基本信息

批准号：
10057606
负责人：
Emily Graves Allen
金额：
$ 25.06万
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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057606
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 men metabolic profile 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

脆弱的X相关震颤/共济失调综合征（FXTA）是一种影响影响的成人神经退行性疾病脆弱的X智力低位1（FMR1）基因的预先定位等位基因（55–200 CGG重复序列）的载体。 FXTA的共同特征包括渐进式意图树，步态共济失调，帕金森氏症和认知衰退。 FXTA的神经病理学标志包括泛素阳性的插图夹杂物。大脑和小脑中浦肯野神经元的辍学。目前，数据在非急速的情况下支持两个 FXTA的独家分子发病机制：1）RNA功能，其中RCGG重复 - 结合蛋白（RBP）通过冗长的RCGG重复序列而在功能上受到限制，而2）重复相关的非AUG（RAN）翻译，通过CGG（或反义CCG）翻译重复会导致产生有毒的同性恋肽，例如FMRPolyg，进而干扰A 各种细胞功能。已经开发了多个小鼠模型来研究这些机制。很多关于与FXTA相关的代谢改变，尤其是在大脑中，以及大多数受影响的小脑。我们以前的工作确定了与 FXTAS发病机理使用我们在小脑Purkinje中表达90 CGG重复的FXTA小鼠模型神经元和表现出FXTA的关键表型特征。通过将全球代谢分析与果蝇遗传屏幕，我们发现鞘脂代谢途径可以调节RCGG重复毒性。与年龄匹配的对照相比，对5个FXTAS验尸大脑的初步研究也确定了鞘脂途径的改变。来自男性的血浆样品的非靶向代谢组分析与非载体男性相比，FXTA的症状确定了鞘脂途径的显着变化。在拟议的研究中，我们将使用其他FXTAS小鼠模型（果蝇）对这些发现进行扩展模型和人类样品。首先，我们将比较表达99的鼠标模型的脂质组谱 CGG重复序列和FMRPolyg蛋白到小鼠模型，该模型表达了扩展的重复，而无需表达FMRPolyg蛋白。此外，我们还将测试与一种靶向β-葡萄糖脑溴酶（GBA）的药物，这是我们发现的鞘脂途径中的关键酶能够调节RCGG重复毒性。我们还将使用其他验尸脑样品和血浆样品已在纵向研究的队列上收集 FXTAS发病机理。我们提出的调查FXTA代谢变化的工作将有助于鉴定生物标志物以及理解疾病的发病机理