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

基本信息

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
项目类别：
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&apos Untranslated Regions 3xTg-AD mouse APP-PS1 Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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

项目摘要

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) 线粒体是动态的，可能在 AD 的发病机制中发挥着关键作用。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促成因素。以及包括 AD 在内的多种神经退行性疾病的进展。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然而，氧化应激诱导的海马神经功能的分子机制。异常的线粒体动力学尚未确定。线粒体动力学和功能可能尚未确定。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线粒体。动力相关蛋白 1 (DRP1)，一种主要的胞质蛋白，在线粒体中易位至线粒体表面 Mff 和 Mid49/51 是线粒体膜蛋白，可将 DRP1 募集到线粒体中。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重要的是，我们的初步数据表明，在神经细胞中，氧化应激会诱导分裂。我们和其他人已经证明 ZCCHC6 的表达可以使 miRNA 尿苷酸化，从而使其无效在我们的初步研究中，我们还发现线粒体网络断裂。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。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 表达异常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因此，我们的研究结果可能与 AD 中的线粒体损伤和裂变有关。对设计新颖的预防和/或治疗策略的 AD 研究产生重大影响。