The role of N6-methyladenosine modified RNA in Alzheimer's disease: Equipment Supplement

N6-甲基腺苷修饰的 RNA 在阿尔茨海默病中的作用：设备补充

• 批准号: 10790273
• 负责人: Benjamin L Wolozin
• 金额: $ 5.6万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10790273
• 关键词: Acceleration; Adaptor Signaling Protein; Adenosine; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyotrophic Lateral Sclerosis; Award; Biological Markers; Brain; Code; Complex; Disease; Disease Progression; Epigenetic Process; Equipment; Exhibits; Functional disorder; Human; Inflammation; Label; Link; Modification; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Pathologic; Pathology; Pathway interactions; RNA; RNA Degradation; RNA metabolism; RNA methylation; RNA-Binding Proteins; Request for Proposals; Risk Factors; Role; Sampling; Severity of illness; Stress; Synapses; Transcript; Untranslated RNA; Vascular Diseases; abeta accumulation; biological adaptation to stress; gene therapy; genotoxicity; induced pluripotent stem cell; innovation; lens; mouse model; response; risk variant; stress granule; tau Proteins; tau aggregation; tau function; therapeutic target; tool; transcriptome; transcriptomics

AWARDED ABSTRACT The accumulation of oligomeric tau (oTau) is known to drive the pathophysiology of Alzheimer’s disease (AD) and related disorders. We recently discovered that oTau functions as part of the translational stress response, forming a complex with methylated RNA (N6-methyl adenosine, m6A) through adapter proteins, such as HNRNPA2B1, which is itself a risk factor for amyotrophic lateral sclerosis. m6A is known to regulate RNA degradation and utilization, and the m6A modification is “read” by adapter proteins. This complex accumulates in stress granules along with other RNA binding proteins (RBPs), many of which are also risk factors for neurodegenerative diseases. We observe a strong increase of m6A in AD highlights, which the importance epigenetic transcriptomics in AD. The m6A pathway provides a powerful new path to elucidate mechanisms of neurodegeneration. The m6A axis also provides an innovative, putative therapeutic target for AD because our studies using an iPSC-based model of AD show that reducing m6A levels reduces tau pathology and delays disease progression, suggesting returning m6A to basal levels is beneficial. Multiple stresses (e.g., β-amyloid (Aβ) aggregation, AD risk genes, vascular dysfunction, inflammation and aging) converge to drive the pathophysiology of AD. Analyzing stress responses through the lens of RNA metabolism and the translational stress response provides a vast tool of molecules for elucidating the stress response in AD. Some RBPs, such as TIA1, HRNPA2B1 and tau appear to be required for responses to synaptic stress, while other RBPs, such as FUS, appear to respond mostly to genotoxic damage. Many RBPs exhibit genetic changes that are linked to neurodegenerative diseases, which emphasizes their disease-relevance. The m6A tag links RBPs with RNA metabolism. Sequencing m6A labeled transcripts provides an additional powerful approach to identify the particular m6A labeled RNA species respond to stresses and disease. Transcripts showing particularly large disease related changes in m6A could provide the basis for new disease biomarkers or represent potential targets for disease-modifying gene therapy. We hypothesize that increases in m6A occur early in disease course in response to tau pathology, enhance the translational stress response and accelerate neurodegeneration. The studies below will determine which molecular and pathological changes correlate most closely with m6A levels, and which show the most dynamic response to m6A reduction. Aim 1 will determine how the m6A transcriptome over the disease course in mouse models of AD/ADRD, examining both coding and noncoding RNA. Aim 2 will determine how the m6A transcriptome varies by disease severity and type in human pathological cases. Aim 3 will determine how m6A contributes to the pathophysiology of tau and neurodegeneration in AD.

获奖摘要 已知寡聚tau（oTau）的积累驱动阿尔茨海默病（AD）的病理生理学， 相关疾病。我们最近发现oTau作为翻译应激反应的一部分发挥作用， 通过接头蛋白与甲基化RNA（N6-甲基腺苷，m6 A）形成复合物，如 HNRNPA 2B 1，其本身是肌萎缩侧索硬化症的危险因素。已知m6 A调节RNA m6 A修饰被衔接蛋白“读取”。这种复合物积累 在应激颗粒中，沿着其他RNA结合蛋白（RBP），其中许多也是 神经退行性疾病我们观察到AD突出显示中m6 A的强烈增加，其重要性 AD中的表观遗传转录组学m6 A通路提供了一个强大的新途径，阐明机制， 神经变性m6 A轴也为AD提供了一个创新的、推定的治疗靶点，因为我们的研究发现， 使用基于iPSC的AD模型的研究表明，降低m6 A水平可减少tau病理学和延迟 疾病进展，表明m6 A恢复到基础水平是有益的。 多重应力（例如，β-淀粉样蛋白（Aβ）聚集、AD风险基因、血管功能障碍、炎症和衰老） 汇聚到驱动AD的病理生理学。从RNA代谢的透镜和植物的生理机制分析植物的胁迫反应 翻译应激反应为阐明AD的应激反应提供了一个广阔的分子工具。一些限制性商业惯例， 例如TIA 1、HRNPA 2B 1和tau似乎是对突触应激的反应所必需的，而其它RBP，例如 FUS似乎主要对遗传毒性损伤有反应。许多限制性商业惯例表现出与以下因素有关的遗传变化： 神经退行性疾病，强调其疾病相关性。m6 A标签将RBP与RNA连接起来 新陈代谢.对m6 A标记的转录物进行测序提供了一种额外的强有力的方法来鉴定特定的转录物。 m6 A标记的RNA种类响应于应激和疾病。成绩单显示特别大的疾病相关 m6 A的变化可以为新的疾病生物标志物提供基础，或代表疾病修饰的潜在靶点。 基因治疗我们假设m6 A的增加发生在疾病过程的早期，以响应tau病理学， 增强翻译应激反应并加速神经退行性变。下面的研究将确定 分子和病理变化与m6 A水平最密切相关，并且显示最动态的 M6 A的减少。目的1将确定m6 A转录组在小鼠疾病过程中的作用 AD/ADRD模型，检查编码和非编码RNA。目标2将决定m6 a如何 在人类病理学病例中，转录组随疾病严重程度和类型而变化。目标3将确定m6 A如何 有助于AD中tau和神经变性的病理生理学。