A Novel RNA Binding Protein Modulates Tau Pathology

一种新型 RNA 结合蛋白调节 Tau 病理学

• 批准号: 9333741
• 负责人: ANITA H. CORBETT
• 金额: $ 19.19万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333741
• 关键词: Address; Affect; Affinity; Age of Onset; Alzheimer' s Disease; Antibodies; Behavioral; Binding; Binding Proteins; Brain; Brain Diseases; Caenorhabditis elegans; Collaborations; Complement; Controlled Study; Critical Pathways; Data; Data Discovery; Deterioration; Disease; Disease Progression; Financial cost; Funding; Gene Expression Regulation; Genes; Genetic Screening; Genetic Transcription; Genets; Goals; Human; Individual; Investigation; Knockout Mice; Laboratories; Letters; Life; Link; MAPT gene; Mammals; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Mus; Mutate; Nerve Degeneration; Neurofibrillary Tangles; Nuclear Family; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Post-Transcriptional Regulation; Precipitation; Proteins; Proteomics; Quality of life; RNA; RNA-Binding Proteins; Research; Resources; Role; Sampling; Series; Spliceosomes; Staining method; Stains; Testing; Time; Transcript; Transgenic Mice; Transgenic Organisms; Zinc Fingers; base; effective therapy; in vivo; insight; member; mouse model; novel; polyadenosine; pre-clinical; protein aggregate; social; tau Proteins; tau aggregation; tau expression; transcriptome; transcriptome sequencing

Project Summary There are over 5 million people in the US currently living with Alzheimer's Disease (AD). Despite the loss of life, deterioration in quality of life, and social and financial costs of this devastating disease, there is still no cure or effective treatment to slow disease progression. A variety of approaches show promise in defining the key molecular changes that underlie pathology in AD. Many of these studies focus on the microtubule associated protein Tau and understanding how Tau contributes to neurodegeneration. A genetic screen for modulators of Tau pathology in C. elegans identified Suppressor of Tau 2 (sut-2). The sut-2 protein is a member of an evolutionarily-conserved family of nuclear, zinc finger polyadenosine RNA binding proteins. The human protein is termed Zinc Finger Cys3 His #14 (ZC3H14) or MSUT2. In our preliminary studies, we have identified ZC3H14 enriched in insoluble aggregates in AD brain. Furthermore, we have identified physical interactions between murine ZC3H14 and components of the RNA spliceosome including the U1-70K protein, which the Seyfried laboratory has linked to Tau pathology. Finally, ZC3H14 binds to the Mapt transcript encoding Tau suggesting a role for ZC3H14 in modulating post-transcriptional processing and/or expression of Tau. Based on our preliminary data and the discovery of sut-2 as a Tau modifier, we hypothesize that ZC3H14 interacts with critical RNA binding proteins and contributes to Tau-mediated pathology. Drawing extensively on resources available in the Alzheimer's Disease Research Center (ADRC) at Emory and our own preliminary data, we propose a collaborative multi-PI (Corbett and Seyfried) approach to test our hypothesis through the following specific aims: Aim 1) Define the spectrum of ZC3H14-interacting proteins in normal and AD brain; and Aim 2) Assess whether a decrease in ZC3H14 levels ameliorates Tau-induced pathology in a mouse model of Tau-mediated pathology and probe potential mechanisms. Our collaborative team is uniquely qualified to perform the proposed studies as 1) we have access to the required patient samples and expertise in proteomics provided by the Emory Proteomics core directed by MPI Seyfried; and 2) we have created the first Zc3h14 (MSUT2) knockout mouse. The homozygous Zc3h14 null (Zc3h14-/-) mice are viable and fertile and available to cross to Tau P301S transgenic mice (Line PS19) to assess whether ZC3H14 modifies Tau phenotypes in mammals. In addition, we will exploit these mice for preliminary analysis of how ZC3H14 regulates Tau expression. The goal of this exploratory proposal is to probe the mechanism by which ZC3H14 contributes to Tau-induced pathology. The long-term goal of our studies is to identify molecular pathways that could be targeted to modulate Tau-induced pathology.

项目摘要 目前美国有超过500万人患有阿尔茨海默病（AD）。尽管失去了 这种毁灭性疾病造成了生命、生活质量恶化以及社会和经济成本，但仍然无法治愈 或有效治疗以减缓疾病进展。有多种方法可以用来定义密钥 AD病理学基础的分子变化。这些研究中的许多集中在微管相关的 Tau蛋白和了解Tau如何促进神经退行性变。一种基因筛选的调节剂， Tau病理学在C. elegans鉴定了Tau 2的抑制子（sut-2）。sut-2蛋白是一个 进化上保守的核锌指聚腺苷RNA结合蛋白家族。人蛋白质 被称为锌指Cys 3 His#14（ZC 3 H14）或MSUT 2。在我们的初步研究中，我们发现 ZC 3 H14在AD脑中富集不溶性聚集体。此外，我们已经确定了物理相互作用 在鼠ZC 3 H14和RNA剪接体的组分之间，包括U1- 70 K蛋白， 与Tau病理学有关。最后，ZC 3 H14与编码Tau的Mapt转录物结合 表明ZC 3 H14在调节Tau的转录后加工和/或表达中的作用。基于 根据我们的初步数据和sut-2作为Tau修饰剂的发现，我们假设ZC 3 H14与Tau相互作用， 与关键的RNA结合蛋白，并有助于Tau介导的病理学。广泛借鉴 埃默里大学阿尔茨海默病研究中心（ADRC）的现有资源和我们自己的初步研究 数据，我们提出了一个合作的多PI（Corbett和Seyfried）的方法来测试我们的假设，通过 目的1）确定正常和AD脑中ZC 3 H14相互作用蛋白的谱; 2）评估ZC 3 H14水平的降低是否改善小鼠中Tau诱导的病理学 Tau介导的病理学模型和探针潜在机制。我们的合作团队是独一无二的 有资格进行拟定研究，因为1）我们可以获得所需的患者样本和专业知识 由MPI Seyfried指导的Emory蛋白质组学核心提供的蛋白质组学; 2）我们已经创建了 第一个Zc 3 h14（MSUT 2）敲除小鼠。纯合子Zc 3 h14 null（Zc 3 h14-/-）小鼠存活且可生育 并且可用于与Tau P301 S转基因小鼠（系PS19）杂交以评估ZC 3 H14是否修饰Tau 哺乳动物的表型此外，我们将利用这些小鼠进行初步分析， 调节Tau表达。该探索性建议的目标是探索ZC 3 H14 导致了Tau诱发的病理学我们研究的长期目标是确定分子途径， 可以靶向调节Tau诱导的病理学。