Role of Mettl3-dependent RNA m6A dysregulation in Alzheimer's disease

Mettl3 依赖性 RNA m6A 失调在阿尔茨海默病中的作用

• 批准号: 10739065
• 负责人: Xiongwei Zhu
• 金额: $ 215.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739065
• 关键词: AD transgenic mice; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animal Model; Behavioral; Binding Proteins; Biogenesis; Bioinformatics; Biological Process; Brain; CREB1 gene; Catalytic Domain; Cell Nucleus; Cell model; Cognitive; Cognitive deficits; Complex; Cytosol; DNA Modification Process; Disease; Environmental Risk Factor; Epigenetic Process; Event; Exclusion; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Hippocampus; Histone Acetylation; In Vitro; Individual; Life Cycle Stages; Mediating; Messenger RNA; Methylation; Methyltransferase; Mitochondria; Modeling; Modification; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Pathogenesis; Pathologic; Pathway interactions; Patients; Play; Prosencephalon; Protein Family; Proteins; Public Health; RNA; RNA Processing; RNA Stability; Reader; Regulation; Regulator Genes; Risk; Role; Signal Transduction; Site; Synapses; Toxic effect; Translations; abeta oligomer; age related neurodegeneration; biological adaptation to stress; cognitive function; drug development; gene function; hippocampal pyramidal neuron; histone modification; in vivo; in vivo Model; insight; interest; knock-down; lifestyle factors; mRNA Stability; mild cognitive impairment; mitochondrial dysfunction; mouse model; neuroinflammation; neuroprotection; novel; overexpression; symptom treatment; synaptic function; therapeutic target

PROJECT SUMMARY/ABSTRACT As a complex and multifactorial disease, a combination of genetics, environmental and lifestyle factors affect ones’ risk of developing AD through complex transcriptional and translational changes in the gene expression in AD brain, however, the mechanisms underlying these changes remain elusive. Analogous to DNA and histone modifications, RNA modifications could also lead to alterations in gene expression which allows extra layers of regulation of gene expression. N6-methyladenosine (m6A) is the most common internal modification in eukaryotic mRNAs which regulates RNA stability, processing, localization, translation. It is involved in various biological processes including mitochondrial function, synaptic function and cognitive function, but the potential role of RNA m6A modification in aging and age-related neurodegenerative diseases including AD is largely unexplored. Studies from my group and several other groups demonstrated METTL3-m6A dysregulation is an early event during the course of AD. METTL3 knockdown in the hippocampus caused AD-related cognitive deficits and neurodegeneration while METTL3 overexpression rescued AβO-induced neuronal/synaptic and cognitive/behavioral deficits, suggesting a critical role of METTL3-m6A dysregulation in the pathogenesis of AD. mRNA of many AD-related genes contain m6A suggesting that METTL3-dependent m6A modification likely have impacts on multiple aspects related to AD. Given that mitochondrial dysfunction plays a critical role in the pathogenesis of AD, it is of particular interest to note that methylation profiling identified multiple m6A sites in mRNAs of key regulators of mitochondrial functions including those involved in mitochondrial biogenesis (i.e., PGC1α and TFAM) and mitochondrial dynamics (i.e., Mfn2 and DLP1). Indeed, METTL3 knockdown caused mitochondrial fragmentation and dysfunction likely through modulation of PGC1α and Mfn2 expression which could contribute to Aβ oligomers-induced mitochondrial dysfunction. Based on these studies, we hypothesized that reduced METTL3-m6A signaling modulates the expression of mitochondrial regulators and contributes to mitochondrial dysfunction and the pathogenesis of AD. Therefore, METTL3 overexpression rescues m6A signaling and mitochondrial gene expression and function and alleviates AD-related deficits. We will determine the mechanisms underlying METTL3 reduction in AD and explore whether and how reduced METTL3 mediates toxic effects of AβO on mitochondrial biogenesis/dynamics and function in AD. Novel animal models with METTL3 overexpression in the forebrain will be crossed with AD transgenic mouse models and carefully characterized. The successful completion of this study will provide novel mechanistic insights into changes in gene expression in AD and will likely establish METTL3-m6A signaling as a promising therapeutic target for drug development in AD, which also have implications of studying other neurodegenerative disorders and aging in general.

项目摘要/摘要 作为一种复杂和多因素的疾病，遗传、环境和生活方式因素的结合会影响 通过基因复杂的转录和翻译变化患上阿尔茨海默病的风险 然而，在AD脑中的表达，这些变化背后的机制仍然不清楚。类似于 DNA和组蛋白修饰、RNA修饰也可能导致基因表达的变化 允许对基因表达进行额外的层级调控。N6-甲基腺苷(M6A)是最常见的体内 真核mRNAs中调节RNA稳定性、加工、定位和翻译的修饰。它是 参与多种生物学过程，包括线粒体功能、突触功能和认知功能 功能，但RNA m6A修饰在衰老和老年相关神经退行性变中的潜在作用 包括阿尔茨海默病在内的疾病在很大程度上是未知的。我的团队和其他几个团队的研究证明 METTL3-M6A异常是AD发病过程中的早期事件。METTL3被击倒在 海马区导致AD相关认知功能障碍和神经变性，METTL3过度表达 挽救了βO诱导的神经元/突触和认知/行为缺陷，表明 METTL3-M6A基因异常在AD发病机制中的作用许多AD相关基因的mRNA中含有M6A 提示依赖METTL3的M6A基因修饰可能对AD相关的多个方面产生影响。 鉴于线粒体功能障碍在阿尔茨海默病的发病机制中起着关键作用，人们对此特别感兴趣 注意，甲基化分析在线粒体关键调节因子的mRNAs中发现了多个m6A位点 功能，包括参与线粒体生物发生的那些(即Pgc1α和TFAM)和线粒体 动力学(即Mfn2和DLP1)。事实上，METTL3基因敲除导致线粒体碎裂和 可能通过调节前列腺素C_1α和Mfn2的表达而导致功能障碍，这可能是导致β的原因之一 寡聚体导致线粒体功能障碍。基于这些研究，我们假设减少了 METTL3-m6A信号调节线粒体调节剂的表达并参与 线粒体功能障碍与阿尔茨海默病的发病机制因此，METTL3过度表达挽救了 M6A信号和线粒体基因的表达和功能，并缓解AD相关的缺陷。 我们将确定AD患者METTL3减少的机制，并探讨是否以及如何 MetTL3降低介导AβO对AD线粒体生物发生/动力学和功能的毒性作用 前脑METTL3过度表达的新型动物模型将与AD转基因小鼠杂交 模型和仔细刻画。这项研究的成功完成将提供新的机制 对AD基因表达变化的洞察，并可能建立METTL3-m6A信号作为一种 AD药物开发的有前景的治疗靶点，这也对研究其他 神经退行性疾病和衰老。