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.

授予摘要 众所周知，寡聚TAU（OTAU）的积累可以推动阿尔茨海默氏病（AD）和 相关疾病。我们最近发现，奥塔（Otau）作为翻译应力反应的一部分， 通过衔接蛋白（例如 HNRNPA2B1本身就是肌萎缩性侧硬化症的危险因素。已知M6A调节RNA 降解和利用以及M6A修饰是通过衔接蛋白“读取”的。这个复合物积累 在胁迫颗粒以及其他RNA结合蛋白（RBP）中，其中许多也是危险因素 神经退行性疾病。我们观察到AD亮点中M6A的大幅度增加，这一点很重要 AD中的表观遗传转录组学。 M6A途径为阐明机制提供了强大的新途径 神经变性。 M6A轴还为AD提供了创新的，推定的治疗目标，因为我们 使用基于IPSC的AD模型的研究表明，降低M6A水平会减少TAU病理学和延迟 疾病进展，表明将M6A返回基本水平是有益的。 多种应力（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） 收敛以驱动AD的病理生理。通过RNA代谢和 翻译应力反应提供了一种庞大的分子工具，用于阐明AD中的应力反应。一些RBP， 例如TIA1，HRNPA2B1和TAU似乎是对突触应激的响应所必需的，而其他RBP，例如 FUS，似乎主要对遗传毒性损伤做出反应。许多RBP暴露了与 神经退行性疾病，强调其疾病 - 疾病。 M6A标签将RBP与RNA链接 代谢。测序M6A标记的成绩单提供了一种额外的强大方法来识别特定 M6A标记为RNA物种对应力和疾病的反应。成绩单显示特别大疾病与疾病有关 M6A的变化可以为新疾病生物标志物提供基础，或代表疾病改良的潜在靶标 基因疗法。我们假设M6A的增加在疾病病程的早期发生，以应对Tau病理学， 增强翻译应力反应并加速神经变性。下面的研究将确定哪个 分子和病理变化与M6A水平最紧密地相关，并且显示最动态的 对M6A降低的响应。 AIM 1将确定小鼠疾病过程中的M6A转录组如何 AD/ADRD的模型，检查编码和非编码RNA。 AIM 2将确定M6A如何 疾病严重程度的转录组变异和人类病理病例的类型。 AIM 3将决定M6A 在AD中有助于TAU和神经退行性的病理生理。