Systematic and mechanistic assessment of the roles of circRNAs in Alzheimer's Disease

环状RNA在阿尔茨海默病中作用的系统和机制评估

• 批准号: 10666760
• 负责人: Sebastian Kadener
• 金额: $ 24.38万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666760
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Animals; Apoptosis; Area; Autophagocytosis; Awareness; Behavior; Behavioral; Brain; Collection; Data; Defect; Development; Disease; Disease Outcome; Disease Progression; Disease model; Drosophila genus; Exons; Eye; Gene Expression; Genetic; Genetic Screening; Genomics; Health; Homeostasis; Human; Impairment; Incidence; Individual; Inflammation; Lead; Libraries; Link; Longevity; Mediating; Methodology; MicroRNAs; Mitochondria; Modeling; Molecular; Motor; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxicity Syndromes; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Phenotype; Post-Translational Protein Processing; Proteins; RNA; RNA metabolism; RNA-Binding Proteins; Regulation; Research; Resources; Role; Surface; System; Testing; Time; Tissues; Whole Organism; Work; age related; aging population; circular RNA; disorder control; experimental study; fly; healthspan; improved; in vivo; knock-down; nervous system disorder; neural; neuroprotection; neurotoxic; overexpression; protein metabolism; screening; success; tau Proteins; tau expression; tau interaction; tool

PROJECT SUMMARY Control of RNA metabolism is emerging as a major hub for regulation in the brain. Therefore, it is not surprising that there is a strong link between perturbation of RNA metabolism and a number of neurological and neurodegenerative diseases. These include Alzheimer’s Disease (AD) in which Tau protein and Aß42 fragments have been shown to interact and/or modulate directly or indirectly RNA binding proteins and RNA metabolism in general. Circular RNAs (circRNAs) are highly abundant RNAs produced by circularization of specific exons. Interestingly, circRNAs accumulate in an age-dependent manner in neural tissues suggesting their relevance to age-related homeostasis and/or pathogenesis. Indeed, specific circRNAs accumulate in the brains of individuals with Parkinson’s and Alzheimer’s diseases. However, how these circRNAs are involved in the pathogenesis of those and other neurodegenerative diseases is largely unknown. We recently developed systems to down- or up-regulate circRNAs in Drosophila. Using these tools, we demonstrated the functionality of these molecules in vivo. We generated a resource to knock down (KD) the 110 more abundant circRNAs and found that KD of particular circRNAs results in different brain-related phenotypes. Interestingly, we identified 35 circRNAs that when knocked down alter lifespan. Further data shows that expression of some circRNAs is toxic for the aging fly, with links to aging and potentially neurodegeneration. In addition, we found that KD of some circRNAs lead to specific behavioral and motor defects, many of which are age-dependent. In addition, we observed changes in the levels of circRNAs in Drosophila models of AD or other neurogenerative diseases. Here we aim to uncover the functions and mechanisms of action of circRNAs during AD. To do so, we will use Drosophila AD models and perform a genomic screening to determine if modulation of individual circRNAs can alter the progression and outcome of the disease. Moreover, we will also test potential mechanisms by which circRNAs could alter AD including nucleation of aggregates, altering mitochondrial function, autophagy, apoptosis, and/or inflammation. In sum, the present proposal will reveal new roles of circRNAs during AD. As we will perform the experiments in a system that has high and functional levels of circRNAs (the fly CNS) the present results will be meaningful and could be later extended to mammalian models. We are aware of the limitations of the AD fly models but this is the only system in which the full extent of interaction with a large number of circRNAs can be assessed. Moreover, as we have already found that some circRNAs alter aging, the chances of success are high. This will be a pioneering work in this new and important area of research and we are confident that our findings will open a new pathway for studying the roles of circRNAs in AD. Our project builds on exciting preliminary results and the unique and constantly evolving expertise of our group.

项目摘要 RNA代谢的控制正在成为大脑调控的主要枢纽。因此不 令人惊讶的是，RNA代谢的扰动和许多神经系统疾病之间存在密切联系。 和神经变性疾病。这些疾病包括阿尔茨海默病（AD），其中Tau蛋白和A β 42 片段已显示直接或间接地与RNA结合蛋白和RNA相互作用和/或调节RNA结合蛋白和RNA结合蛋白。 新陈代谢一般。环状RNA（circRNA）是通过环化RNA而产生的高度丰富的RNA。 特定外显子。有趣的是，circRNA在神经组织中以年龄依赖性的方式积累，这表明 它们与年龄相关的稳态和/或发病机制的相关性。事实上，特定的circRNA积累在 帕金森和阿尔茨海默病患者的大脑。然而，这些circRNA是如何 参与这些和其他神经退行性疾病的发病机制的基因在很大程度上是未知的。 我们最近开发了下调或上调果蝇circRNA的系统。利用这些工具，我们 证明了这些分子在体内的功能。我们生成了一个资源来击倒（KD） 110种更丰富的circRNA，并发现特定circRNA的KD导致不同的脑相关性 表型有趣的是，我们发现了35种circRNA，当被敲低时，它们会改变寿命。进一步的数据 表明一些circRNA的表达对衰老的苍蝇是有毒的，与衰老有关， 神经变性此外，我们发现一些circRNA的KD导致特定的行为和运动 缺陷，其中许多是年龄依赖性的。此外，我们还观察到在24小时内， AD或其他神经退行性疾病的果蝇模型。在这里，我们的目标是揭示功能， CircRNA在AD期间的作用机制。为此，我们将使用果蝇AD模型并执行 基因组筛选，以确定单个circRNA的调节是否可以改变进展和结果 疾病。此外，我们还将测试circRNA改变AD的潜在机制，包括 聚集体的成核、改变线粒体功能、自噬、凋亡和/或炎症。 总之，本研究将揭示circRNA在AD中的新作用。因为我们将执行 在具有高水平和功能水平的circRNA（苍蝇CNS）的系统中进行的实验，本结果将 有意义，以后可以扩展到哺乳动物模型。我们知道广告的局限性 但这是唯一一个与大量circRNA相互作用的完整程度 可以被评估。此外，正如我们已经发现的，一些circRNA改变衰老， 成功是高。这将是这一新的重要研究领域的开创性工作，我们正在 相信我们的发现将为研究circRNA在AD中的作用开辟一条新途径。我们的项目 建立在令人兴奋的初步结果和我们集团独特且不断发展的专业知识之上。