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

获奖摘要 寡聚体tau(OTau)的积累已知推动阿尔茨海默病(AD)的病理生理和 相关的障碍。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的RNA(N6-甲基腺苷，m6A)形成复合体，如 HnRNPA2B1本身就是肌萎缩侧索硬化症的危险因素。已知M6A可调节RNA 降解和利用，m6A修饰被适配蛋白“读取”。这个复合体积累起来 在压力颗粒和其他RNA结合蛋白(RBPs)中，其中许多也是 神经退行性疾病。我们观察到AD患者M6A的强劲增加，这一点的重要性 AD中的表观遗传转录组。M6A通路为阐明肿瘤的发病机制提供了一条新的有效途径。 神经退行性变。M6A轴也为AD提供了一个创新的、假定的治疗靶点，因为我们的 使用基于IPSC的AD模型的研究表明，降低m6A水平可以减少tau病理和延迟 疾病进展，提示将m6A恢复到基础水平是有益的。 多重应激(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) 汇聚推动AD的病理生理学。从RNA新陈代谢的角度分析应激反应 翻译应激反应为阐明阿尔茨海默病的应激反应提供了大量的分子工具。一些限制性商业惯例， 如TIA1、HRNPA2B1和tau似乎是对突触应激反应所必需的，而其他限制性商业惯例，如 FUS似乎主要对基因毒性损伤做出反应。许多限制性商业惯例表现出基因变化，这些变化与 神经退行性疾病，强调它们与疾病的相关性。M6A标签将限制性商业惯例与核糖核酸联系起来 新陈代谢。对m6A标记的转录本进行测序提供了另一种有效的方法来识别特定的 M6A标记的RNA物种对压力和疾病做出反应。显示与疾病相关的特别大的成绩单 M6A的变化可能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 基因疗法。我们假设M6A的增加发生在疾病过程的早期，以响应tau病理， 增强翻译应激反应，加速神经退行性变。下面的研究将确定 分子和病理变化与m6a水平的相关性最密切，并且显示出最动态的变化。 对m6A减少的反应。目标1将确定m6A转录组如何在小鼠的疾病过程中 AD/ADRD模型，同时检查编码和非编码RNA。目标2将决定M6A如何 在人类病理病例中，转录组因疾病严重程度和类型而异。目标3将决定M6A如何 在AD的tau和神经退行性变的病理生理学方面有贡献。

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.