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

已知寡聚tau （oTau）的积累可驱动阿尔茨海默病（AD）和相关疾病的病理生理。我们最近发现oTau作为翻译应激反应的一部分起作用，通过适配蛋白（如HNRNPA2B1）与甲基化RNA （n6 -甲基腺苷，m6A）形成复合物，这本身就是肌萎缩侧索硬化症的危险因素。已知m6A调节RNA降解和利用，并且m6A修饰被适配蛋白“读取”。这种复合物与其他RNA结合蛋白（rbp）一起在应激颗粒中积累，其中许多也是神经退行性疾病的危险因素。我们观察到阿尔茨海默病中m6A的强烈增加，这突出了表观转录组学在阿尔茨海默病中的重要性。m6A通路为阐明神经退行性变的机制提供了强有力的新途径。m6A轴也为阿尔茨海默病提供了一个创新的、假定的治疗靶点，因为我们使用基于ipsc的阿尔茨海默病模型的研究表明，降低m6A水平可以减少tau病理并延缓疾病进展，这表明将m6A恢复到基础水平是有益的。多种应激（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）共同驱动AD的病理生理。通过RNA代谢和翻译应激反应的角度分析应激反应，为阐明AD的应激反应提供了大量的分子工具。一些rbp，如TIA1， HRNPA2B1和tau似乎是对突触应激反应所必需的，而其他rbp，如FUS，似乎主要对基因毒性损伤作出反应。许多rbp表现出与神经退行性疾病相关的遗传变化，这强调了它们与疾病的相关性。m6A标签将rbp与RNA代谢联系起来。测序m6A标记的转录本提供了一种额外的强大方法来鉴定特定的m6A标记的RNA物种对压力和疾病作出反应。在m6A中显示特别大的疾病相关变化的转录本可以为新的疾病生物标志物提供基础或代表疾病修饰基因治疗的潜在靶点。我们假设m6A的增加发生在疾病早期，以响应tau病理，增强翻译应激反应并加速神经退行性变。下面的研究将确定哪些分子和病理变化与m6A水平最密切相关，哪些对m6A减少表现出最动态的反应。目的1将通过检测编码RNA和非编码RNA，确定m6A转录组在AD/ADRD小鼠模型中的病程。目的2将确定人类病理病例中m6A转录组如何随疾病严重程度和类型而变化。目的3将确定m6A如何参与AD中tau和神经退行性变的病理生理。

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 which highlights the importance of epi-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 that 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 the 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 non-coding 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.