Reverse electron transport and tauopathy

反向电子传递和tau蛋白病

• 批准号: 10740115
• 负责人: Bingwei Lu
• 金额: $ 19.36万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740115
• 关键词: Affect; Aging; Alzheimer' s Disease; Amyloid; Animal Model; Bacterial Infections; Binding; Bioenergetics; Biological; Brain; Brain Diseases; Cognitive deficits; Complex; Defect; Development; Disease; Drug Targeting; Electron Transport; Electrons; Failure; Functional disorder; Genetic; Goals; Human; Induced pluripotent stem cell derived neurons; Infection; Inner mitochondrial membrane; Link; Longevity; MAPT gene; Macrophage Activation; Microtubules; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Mus; NADH; Nerve Degeneration; Neurodegenerative Disorders; Outcome; Pathogenicity; Pathologic; Physiological; Physiological Processes; Post-Translational Protein Processing; Process; Production; Proteins; Proton Pump; Reactive Oxygen Species; Reperfusion Injury; Respiratory Chain; Role; Senile Plaques; Signal Transduction; Site; Succinates; Tauopathies; Testing; Therapeutic; Thermodynamics; Toxic effect; Ubiquinone; Vaccination; age related; age related neurodegeneration; arm; cancer stem cell; cerebral atrophy; cognitive function; cytochrome c; disease phenotype; drug candidate; fly; human disease; improved; in vivo; induced pluripotent stem cell; inhibitor; interest; knock-down; mitochondrial dysfunction; mouse model; neuron loss; neuroprotection; new therapeutic target; notch protein; novel; oxidation; pharmacologic; prevent; response; small molecule; tau Proteins; tau aggregation; tau interaction; tau mutation; therapeutic development; therapeutic target; ubiquinol; β-amyloid burden

Project Summary Hyperphosphorylation and aggregation of microtubule-associated tau is a pathological hallmark of tauopathies including Alzheimer's disease (AD). In AD, tau abnormality correlates with neuronal loss and cognitive deficits better than amyloid burden. There is increasing interest in the development of tau-targeting drugs, for AD as well as other tauopathies. Developing effective tau-targeting drugs requires a deeper and broader understanding of the pathogenic mechanisms of tau. Recent studies have revealed extensive tau interaction with mitochondrial proteins. Intriguingly, studies in animal models and humans have uncovered a specific link between tau and mitochondrial complex-I (C-I) dysfunction, although the exact mechanism is unclear. C-I is the largest multisubunit complex of the respiratory chain containing 45 subunits in humans. Under normal physiological conditions, C-I catalyzes the oxidation of NADH to NAD+, initiates the transfer of electrons along the electron transport chain (ETC) from NADH to ubiquinone, accompanied by proton pumping to generate the gradient across the inner mitochondrial membrane needed for ATP production. Defective C-I is a frequent cause of mitochondrial dysfunction linked to human diseases. In addition to bioenergetic failure, reactive oxygen species (ROS) production is intimately associated with mitochondrial dysfunction. Various studies have implicated reverse electron transfer (RET) at C-I as the major site of mitochondrial ROS production. Under certain thermodynamic conditions, for example when forward electron transport (FET) is blocked or when succinate accumulates to high level, RET can occur along C-I, moving electrons from ubiquinol (CoQ10H2) to NAD+, producing a significant amount of ROS (RET-ROS) in the process. RET-ROS has been linked to physiological processes such as macrophage activation in response to bacterial infection. However, excessive RET- ROS is implicated in disease conditions such as ischemia-reperfusion injury. Another outcome of RET is the conversion of NAD+ to NADH, thereby decreasing NAD+ and lowering NAD+/NADH ratio, which has been linked to aging and age-related diseases. In preliminary studies, we have shown that inhibition of RET by a small molecule drug that targets NDUFS3, or partial knockdown of NDUFS3 by genetic means, extends lifespan and rescues age- related disease phenotypes in fly models. Excitingly, our preliminary studies generated compelling evidence that pharmacological inhibition of RET can rescue cognitive deficits and neurodegeneration and extend the lifespan of tauopathy mouse models. The goal of this study is to use in vivo mouse models and human iPSC-derived neuronal models to test our central hypothesis that RET is altered in tauopathy, that tau interacts with C-I components to affect RET, and that pharmacological or genetic targeting of NDUFS3 can restore RET and offer neuroprotection. Despite overwhelming evidence implicating defective mitochondria in general, and C-I in particular, in tauopathies, mitochondria and C-I have not been the focus of therapeutic development targeting tauopathies. Positive outcomes from this project will help validate RET at C-I as a viable therapeutic target and stimulate interests in the development of RET modulators as drug candidates for the treatment of tauopathies and possibly other brain diseases.

项目摘要 微管相关tau蛋白的过度磷酸化和聚集是tau蛋白病的病理标志 包括阿尔茨海默病（AD）。在AD中，tau蛋白异常与神经元丢失和认知缺陷的相关性更好 比淀粉样蛋白负担更大。对于开发用于AD以及其他疾病的tau靶向药物的兴趣越来越大。 tau蛋白病开发有效的tau靶向药物需要对致病性 Tau的机制最近的研究揭示了广泛的tau蛋白与线粒体蛋白的相互作用。有趣的是， 在动物模型和人类中的研究已经揭示了tau蛋白和线粒体复合物-I（C-I）之间的特定联系 功能障碍，尽管确切的机制尚不清楚。C-I是呼吸链中最大的多亚基复合物 含有45个亚基在正常生理条件下，C-I催化NADH氧化为 NAD+启动电子沿着电子传递链（ETC）从NADH到泛醌的转移， 伴随着质子泵送，以产生ATP所需的线粒体内膜梯度 生产C-I缺陷是与人类疾病相关的线粒体功能障碍的常见原因。除了 在生物能量衰竭中，活性氧（ROS）的产生与线粒体功能障碍密切相关。 许多研究表明，C-I区的反向电子转移（RET）是线粒体ROS的主要位点 生产在某些热力学条件下，例如当正向电子传输（FET）被阻断时， 或者当琥珀酸积累到高水平时，RET可以沿着C-I发生，从泛醇（CoQ 10 H2）移动电子。 NAD+，在此过程中产生大量的ROS（RET-ROS）。RET-ROS与 生理过程，例如响应于细菌感染的巨噬细胞活化。然而，过度的RET- ROS与疾病状况如缺血-再灌注损伤有关。可再生能源技术的另一个成果是 NAD+转化为NADH，从而减少NAD+并降低NAD+/NADH比率，这与 衰老和与年龄有关的疾病。在初步研究中，我们已经表明，小分子抑制RET， 靶向NDUFS 3的药物，或通过遗传手段部分敲除NDUFS 3，延长寿命并挽救年龄- 相关疾病表型。令人兴奋的是，我们的初步研究产生了令人信服的证据， RET的药理学抑制可以挽救认知缺陷和神经退行性变， tau蛋白病小鼠模型。本研究的目的是使用体内小鼠模型和人iPSC衍生的神经元细胞， 模型来检验我们的中心假设，即RET在tau蛋白病中改变，tau蛋白与C-I组分相互作用， RET，并且NDUFS 3的药理学或遗传靶向可以恢复RET并提供神经保护。尽管 压倒性的证据表明，在tau蛋白病中，线粒体一般有缺陷，特别是C-I， 线粒体和C-I不是靶向Tau蛋白病的治疗开发的焦点。积极成果 从这个项目将有助于验证RET在C-I作为一个可行的治疗目标，并激发兴趣的发展 RET调节剂作为候选药物用于治疗tau蛋白病和可能的其他脑疾病。