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.

项目概要 线粒体功能障碍是患者大脑中易感神经元的一个早期显着特征 阿尔茨海默病 (AD)，可能在 AD 的发病机制中发挥着关键作用。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，过度 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影响因素 以及包括 AD 在内的多种神经退行性疾病的进展。反应性产量增加 氧簇（ROS）和疾病依赖性线粒体功能丧失可能是导致线粒体功能丧失的原因 AD 中海马神经元功能的影响。然而，氧化应激诱导的分子机制 异常的线粒体动力学尚未确定。线粒体动力学和功能可能是 由与线粒体裂变相关的因子失调调节。裂变的主要执行者是 动力相关蛋白 1 (DRP1)，一种主要的胞浆蛋白，在线粒体中易位至线粒体表面 以调解裂变。 Mff 和 Mid49/51 是线粒体膜蛋白，可将 DRP1 招募到 线粒体进行裂变。众所周知，Mff 和 Mid49 的表达是转录后的 受特定 miRNA 调节，但尚不清楚为什么这种调节失败导致线粒体增加 公元的裂变。重要的是，我们的初步数据表明，在神经元细胞中，氧化应激会诱导 我们和其他人已经证明 ZCCHC6 的表达可以使 miRNA 尿苷酸化，从而使其无效 在调节基因表达方面。在我们的初步研究中，我们还发现线粒体网络碎片 具有诱导氧化应激的 N2a 神经元和调节线粒体裂变的基因（Mff、Mid49） 上调，而预测调节其表达的 miRNA 则下调。因此，我们的基本 假设是“神经元中氧化应激诱导的 Zcchc6 通过以下方式促进 AD 发病机制： 通过尿苷化使调节线粒体裂变因子的特定 miRNA 无效， 增强线粒体裂变，抑制 ZCCHC6 有可能抑制和/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 AD 中线粒体功能障碍的因果作用 ZCCHC6 异常表达介导神经元氧化应激诱导的线粒体碎片 两种临床前模型中 Zcchc6 的体外和体内耗竭对 AD 和 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的生物学和临床相关性 应激诱导的 Zcchc6 上调和 miRNA 尿苷化调节特征基因的表达 与 AD 中的线粒体损伤和分裂有关。因此，我们的研究结果很可能是 对设计新颖的预防和/或治疗策略的 AD 研究产生重大影响。