Metabolic Dysregulation in FXTAS Pathogenesis

脆性X相关性震颤/共济失调综合征（FXTAS）是一种成人发病的神经退行性疾病， 脆性X智力低下1（FMR 1）基因的前突变等位基因（55 - 200 CGG重复）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、帕金森综合征和认知功能障碍。 下降FXTAS的神经病理学标志包括贯穿全身的泛素阳性核内包涵体。 小脑浦肯野神经元明显缺失。目前，数据支持两个非相互 FXTAS的唯一分子发病机制：1）RNA功能获得，其中rCGG重复- 结合蛋白（RBP）通过长rCGG重复序列的螯合而在功能上受到限制，以及2） 重复相关的非AUG（RAN）翻译，其中通过CGG（或反义CCG）翻译 重复序列导致产生有毒的同源多肽，如FMRpolyG，其反过来又干扰细胞的增殖。 各种细胞功能。已经开发了多种小鼠模型来研究这些机制。多 关于FXTAS相关的代谢改变，特别是在大脑中， 受影响最严重的区域小脑我们以前的工作确定了与以下因素相关的代谢改变： FXTAS发病机制使用我们的FXTAS小鼠模型，在小脑浦肯野表达90个CGG重复序列 神经元，并表现出FXTAS的关键表型特征。通过将全局代谢分析与 果蝇遗传筛选中，我们发现鞘脂代谢途径可以调控rCGG重复序列 毒性一项对5个FXTAS死后大脑与年龄匹配的对照组进行的初步研究也发现， 鞘脂途径的改变。男性患者血浆样本的非靶向代谢组学分析 FXTAS的症状与非携带者男性相比，在鞘脂途径中鉴定出显著改变。 在拟议的研究中，我们将使用其他FXTAS小鼠模型，果蝇， 模型和人体样本。首先，我们将比较表达99 将CGG重复序列和FMRpolyG蛋白与表达扩增的重复序列而不表达扩增的重复序列的小鼠模型进行比较。 表达FMRpolyG蛋白。此外，我们将测试在具有以下特征的果蝇中FXTAS发病机制的改善： 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。我们还将研究FXTAS患者的特征， 尸检脑样本和血浆样本，这些样本是在一个研究队列中收集的， FXTAS发病机制。我们提出的研究FXTAS中代谢变化的工作将有助于 生物标志物的鉴定以及了解疾病的发病机制

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