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 作为一种复杂而多因素的疾病，遗传学，环境和生活方式因素的组合影响 通过复杂的转录和翻译变化来开发广告的风险 然而，在AD大脑中的表达，这些变化的基础机制仍然难以捉摸。类似于 DNA和组蛋白修饰，RNA修饰也可能导致基因表达改变，这 允许额外的基因表达调节层。 N6-甲基二宁（M6A）是最常见的内部 在调节RNA稳定性，加工，定位，翻译的真核mRNA中的修饰。这是 参与各种生物学过程，包括线粒体功能，突触功能和认知 功能，但是RNA M6A修饰在衰老和年龄相关的神经退行性中的潜在作用 包括广告在内的疾病在很大程度上是意外的。我小组和其他几个小组的研究证明了 METTL3-M6A失调是AD过程中的早期事件。 Mettl3敲低 海马引起与广告相关的认知定义和神经变性，而METTL3过表达 营救了AβO诱导的神经元/突触和认知/行为缺陷，这表明 AD发病机理中的METTL3-M6A失调。许多与广告相关基因的mRNA包含M6a 表明依赖Mettl3的M6A修饰可能会对与AD相关的多个方面产生影响。 鉴于线粒体功能障碍在AD的发病机理中起关键作用，因此特别感兴趣 请注意，甲基化谱分析在线粒体关键调节剂的mRNA中鉴定了多个M6A位点 功能包括参与线粒体生物发生（即PGC1α和TFAM）和线粒体的功能 动力学（即MFN2和DLP1）。确实，mettl3敲低引起线粒体碎片和 功能障碍可能通过调节PGC1α和MFN2表达，这可能有助于Aβ 低聚物诱导的线粒体功能障碍。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，并有助于 线粒体功能障碍和AD的发病机理。因此，METTL3过表达救援 M6A信号传导和线粒体基因表达和功能，并减轻与广告相关的缺陷。 我们将确定AD中METTL3降低的基础机制，并探索是否以及如何以及如何 降低的METTL3介导了AβO对AD中线粒体生物发生/动力学和功能的毒性作用。 前脑中具有Mettl3过表达的新型动物模型将与AD转基因小鼠交叉 模型并精心塑造。这项研究的成功完成将提供新颖的机械 对AD中基因表达变化的变化的见解，可能会建立Mettl3-M6A信号作为一个 AD的药物开发的有希望的治疗靶标，这也具有研究其他的含义 神经退行性疾病和衰老。