CGG repeat associated translation in Fragile X-associated Tremor/Ataxia Syndrome-Diversity Supplement

脆性 X 相关震颤/共济失调综合征中的 CGG 重复相关翻译 - 多样性补充剂

• 批准号: 8849600
• 负责人: Peter K Todd
• 金额: $ 4.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8849600
• 关键词: 5' Untranslated Regions; Address; Affect; Amino Acids; Animal Model; Behavior assessment; Behavioral; Binding; Biochemical; Biological Models; Biology; Brain; Brain Diseases; CGG repeat; CGG repeat expansion; Case Study; Cell Culture Techniques; Cells; Codon Nucleotides; Complex; Data; Degenerative Disorder; Disease; Drosophila genus; Exhibits; FMR1; FMR1 Gene; FXTAS; Fragile X Gene; Fragile X Syndrome; Functional RNA; Gene Mutation; Genes; Goals; Hair; Homo; Inherited; Initiator Codon; Knock-in Mouse; Light; Location; Mammals; Measures; Mediating; Messenger RNA; Modeling; Motor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nucleotides; Open Reading Frames; Pathogenesis; Pathogenicity; Pathologic; Patients; Peat; Peptide Initiation Factors; Phenotype; Physiological; Process; Production; Proteins; RNA; RNA Helicase; RNA Splicing; RNA-Binding Proteins; Relative (related person); Research; Research Project Grants; Ribosomes; Role; Scanning; Series; Structure; Surface; Symptoms; Toxic effect; Transcript; Transgenic Organisms; Translating; Translation Initiation; Translations; Ubiquitin; United States; Work; base; clinical phenotype; cryptic protein; fly; human disease; improved; in vivo; insight; mouse model; new therapeutic target; novel; polyglycine; prevent; protein aggregate; protein aggregation; protein misfolding; public health relevance; therapeutic development; therapeutic target

Title: CGG repeat associated translation in Fragile X-associated Tremor/Ataxia Syndrome. Abstract: Dominantly inherited nucleotide repeat expansion disorders are thought to elicit neurodegeneration in one of two ways: 1) The repeat as RNA can bind to and sequester specific proteins, preventing them from performing their normal functions; or 2) If the repeat is translated into protein, the repetitive amino acid expansion can trigger toxicity through a variety of mechanisms including protein misfolding and aggregation. Traditionally, the dominant contribution of each pathogenic mechanism has been suggested by the repeat's location within the disease gene, with exonic repeats exerting toxicity primarily as protein and non-exonic repeats presumably acting via RNA-mediated mechanisms. Recent data, however, indicate that repeats in "non-coding" regions of transcripts can be aberrantly translated into proteins through Repeat Associated Non- AUG initiated (RAN) translation. In light of this new finding, defining the relative contributions of RNA- and protein-mediated toxic processes in each repeat expansion disorder has surfaced as a critical issue in the field. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is an inherited neurodegenerative disorder that results from a CGG repeat expansion at the beginning of the fragile X gene, FMR1. It is characterized pathologically by the formation of proteinaceous inclusions in the brains of patients. Work to date suggests that the repeat is toxic as RNA, but our group recently showed that the CGG repeat expansion also elicits RAN translation ("CGG RAN translation") to produce an aggregation-prone, homopolymeric polyglycine containing protein. This protein aggregates in model systems and is present in inclusions in FXTAS disease brain. In this proposal, we will determine whether the CGG repeat in FXTAS triggers neurodegeneration as RNA, as a toxic protein, or both, and then interrogate how this newly discovered RAN translation occurs mechanistically. To address these questions, we will utilize new fly models of FXTAS to determine the relative abilities of CGG repeats as RNA and as RAN translated proteins to elicit neurodegeneration. We will then extend these findings to pathological and behavioral assessments of two knock-in mouse models of FXTAS that differ in their ability to support CGG RAN translation. In parallel, we will employ a series of biochemical and cell-based approaches to explore the mechanisms underlying CGG RAN translation. These studies should provide critical insight into FXTAS pathogenesis while offering a relevant case-study for other repeat expansion disorders, and in the process facilitate the identification of proximal therapeutic targets based on improved understanding of disease mechanisms.

标题：脆弱的X相关震颤/共济失调综合征中的CGG重复相关翻译。 抽象的： 据认为，主要遗传的核苷酸重复膨胀障碍被认为引起神经退行性疾病。 两种方式：1）重复作为RNA可以结合并隔离特定的蛋白质，以防止它们 执行其正常功能；或2）如果重复翻译成蛋白质，则重复氨基酸 扩张可以通过多种机制引发毒性，包括蛋白质错误折叠和聚集。 传统上，重复提出了每种病原机制的主要贡献 疾病基因中的位置，外显子重复施加毒性主要作为蛋白质和非外观 重复大概是通过RNA介导的机制作用的。但是，最近的数据表明重复 转录本的“非编码”区域可以通过重复相关的非 - 8月开始（RAN）翻译。鉴于这一新发现，定义了RNA和RNA的相对贡献 蛋白质介导的每种重复扩张障碍中的毒性过程在现场浮出水面。 脆弱的X相关震颤/共济失调综合征（FXTA）是一种遗传性神经退行性疾病，导致 从脆弱X基因开始时的CGG重复膨胀，FMR1。它的特征在病理上 通过在患者大脑中形成蛋白质夹杂物。迄今为止的工作表明重复是 有毒作为RNA，但我们的小组最近表明，CGG重复扩展也引起了翻译 （“ CGG RAN翻译”）生产含有蛋白质的易构型，均聚糖聚糖。这 模型系统中的蛋白质聚集体存在于FXTAS病大脑中的夹杂物中。在这个建议中，我们 将确定FXTA中的CGG重复是否触发神经变性为RNA，作为有毒蛋白或 两者都质疑这种新发现的跑步是如何机械出现的。解决 这些问题，我们将利用FXTA的新飞行模型来确定CGG重复的相对能力为 RNA并将蛋白转换为引起神经退行性。然后，我们将把这些发现扩展到 两个FXTA的敲门小鼠模型的病理和行为评估，其能力有所不同 支持CGG运行翻译。同时，我们将采用一系列生化和基于细胞的方法来 探索CGG启动翻译的机制。这些研究应提供对 FXTAS发病机理在为其他重复扩张障碍提供相关病例研究时，在 过程促进基于对疾病的改善的了解，促进近端治疗靶点 机制。