Mechanism of ZCCHC6 Regulation of Mitochondrial Dysfunction In Alzheimer's Disease

ZCCHC6调节阿尔茨海默病线粒体功能障碍的机制

• 批准号: 10358830
• 负责人: Tariq M Haqqi
• 金额: $ 75.14万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358830
• 关键词: 3' Untranslated Regions; 3xTg-AD mouse; APP-PS1; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; American; Amyloid deposition; Biological; Brain; Breeding; Cell Death; Cells; Confocal Microscopy; Data; Defect; Degenerative polyarthritis; Development; Disease; Dynamin; Enzymes; Event; Fibrinogen; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genetic Translation; Goals; Hippocampus (Brain); Human; Immunofluorescence Immunologic; Impaired cognition; Impairment; In Vitro; Knockout Mice; Literature; Mediating; Membrane Potentials; Methods; MicroRNAs; Mitochondria; Mitochondrial Membrane Protein; Molecular; Mouse Strains; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nucleotides; Organelles; Oxidative Stress; Pathogenesis; Pathologic; Patients; Plasmids; Play; Pre-Clinical Model; Preventive; Production; Proteins; RNA; Reactive Oxygen Species; Regulation; Reporter; Reporting; Research; Risk Factors; Role; Senile Plaques; Small Interfering RNA; Stress; Structure; Surface; Tail; Testing; Therapeutic; Tissue Banks; Transferase; Up-Regulation; aged; brain tissue; clinically relevant; cognitive function; design; gene repression; human disease; in vivo; mRNA Expression; miRNA expression profiling; mitochondrial dysfunction; mitochondrial membrane; mouse model; mutant; neuron loss; neuropathology; novel; precision medicine; prevent; recruit; spatiotemporal; tissue degeneration; transgenic model of alzheimer disease; uridylate

PROJECT SUMMARY Mitochondrial dysfunction is an early prominent feature in susceptible neurons in the brain of patients with Alzheimer's disease (AD), which likely plays a critical role in the pathogenesis of AD. Mitochondria are dynamic organelles that undergo continual fission and fusion events. Recent advances indicate that excessive mitochondrial division (fission) is associated with functional defects and is implicated in multiple human diseases including neurodegenerative diseases. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) and disease-dependent loss of mitochondrial function are likely causally involved in loss of hippocampal neuronal function in AD. However, molecular mechanisms underlying oxidative stress-induced abnormal mitochondrial dynamics are yet to be determined. Mitochondrial dynamics and function may be modulated by dysregulation of factors associated with mitochondrial fission. The major executor of fission is the dynamin related protein 1 (DRP1), a mainly cytosolic protein which translocates to the mitochondrial surface in order to mediate fission. Mff and Mid49/51 are mitochondrial membrane proteins that recruit DRP1 to the mitochondria for fission. It is well established that expression of Mff and Mid49 are post-transcriptionally regulated by specific miRNAs but it is not known why this regulation fails resulting in the increased mitochondrial fission in AD. Importantly, our preliminary data demonstrated that in neuronal cells oxidative stress induce the expression of ZCCHC6 which has been shown by us, and others, to uridylate miRNAs rendering them ineffective in regulating gene expression. In our preliminary studies we also found mitochondrial network fragmentation in N2a neurons with induced oxidative stress and that genes that regulate mitochondrial fission (Mff, Mid49) were upregulated and miRNAs predicted to regulate their expression were downregulated. Therefore, our basic hypothesis is that “Oxidative stress induced Zcchc6 in neurons contributes to AD pathogenesis by rendering specific miRNAs that regulate mitochondrial fission factors ineffective by uridylation which enhance mitochondrial fission and that inhibiting ZCCHC6 has the potential to inhibit and/or reverse mitochondrial dysfunction in AD”. To test this hypothesis, we will characterize in detail the causal role of aberrant ZCCHC6 expression in mediating oxidative stress-induced mitochondrial fragmentation in neurons in vitro and the impact of in vivo depletion of Zcchc6 in two preclinical models on the development of AD and cognitive impairment. Our findings will allow us to understand the biological and clinical relevance of oxidative stress-induced upregulation of Zcchc6 and miRNA uridylation to regulate expression of signature genes associated with mitochondrial impairment and fission in AD. Therefore, the results of our study would likely have a major impact on AD research toward designing novel preventive and/or therapeutic strategies.

项目摘要 线粒体功能障碍是脑内易感神经元的早期显著特征， 阿尔茨海默病（Alzheimer's disease，AD）是阿尔茨海默病（Alzheimer's disease，AD）的一种重要的病理类型。线粒体是动态的 经历持续裂变和融合事件的细胞器。最近的进展表明， 线粒体分裂（裂变）与功能缺陷有关，并与多种人类疾病有关 包括神经退行性疾病。氧化应激已被认为是衰老的一个促成因素 以及多种神经退行性疾病包括AD的进展。增加反应性生产 氧自由基（ROS）和疾病依赖性线粒体功能丧失可能与线粒体功能丧失有关。 海马神经元的功能。然而，氧化应激诱导的分子机制， 异常线粒体动力学尚待确定。线粒体动力学和功能可能是 通过与线粒体分裂相关的因子失调来调节。裂变的主要执行者是 发动蛋白相关蛋白1（DRP 1），主要是胞质蛋白，其易位至线粒体表面， 为了调解裂变。Mff和Mid 49/51是线粒体膜蛋白，它们将DRP 1募集到线粒体膜上。 线粒体进行分裂。已经确定Mff和Mid 49的表达是转录后的。 由特定的miRNAs调节，但尚不清楚为什么这种调节失败，导致线粒体 AD中的裂变重要的是，我们的初步数据表明，在神经元细胞中，氧化应激诱导神经元细胞凋亡。 ZCCHC 6的表达已经被我们和其他人所证实，它使miRNA尿苷酸化，使它们无效 在调节基因表达方面。在我们的初步研究中，我们还发现了线粒体网络断裂， N2 a神经元具有诱导的氧化应激，并且调节线粒体分裂的基因（Mff，Mid 49） 上调和预测调节其表达的miRNA下调。因此，我们的基本 假设是“氧化应激诱导的神经元中的Zcchc 6通过以下方式促进AD发病机制： 通过尿苷酸化使调节线粒体分裂因子的特异性miRNA无效， 增强线粒体分裂和抑制ZCCHC 6具有抑制和/或逆转 AD中的线粒体功能障碍”。为了检验这一假设，我们将详细描述 ZCCHC 6异常表达介导氧化应激诱导的神经元线粒体断裂 在两个临床前模型中Zcchc 6的体外和体内消耗对AD发展的影响， 认知障碍我们的研究结果将使我们能够了解氧化应激的生物学和临床相关性。 应激诱导Zcchc 6上调和miRNA尿苷化调控特征基因表达 与AD中线粒体损伤和分裂相关。因此，我们的研究结果可能会 对AD研究设计新的预防和/或治疗策略产生重大影响。