Reverse electron transport and tauopathy

反向电子传递和tau蛋白病

基本信息

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
项目类别：
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&apos 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

项目摘要

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的高磷酸化和聚集是陶氏病的病理标志包括阿尔茨海默氏病（AD）。在AD中，Tau异常与神经元丧失和认知缺陷有关比淀粉样蛋白负担。对于AD以及其他 tauopathies。开发有效的tau靶向药物需要对病原体有更深入的了解 tau的机制。最近的研究揭示了与线粒体蛋白的广泛相互作用。有趣的是，动物模型和人类的研究发现了Tau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育种复合物在人类中包含45个亚基。在正常的生理条件下，C-I催化NADH的氧化 NAD+，启动电子沿电子传输链（ETC）从NADH到泛氨基酮的转移，伴有质子抽水，以产生ATP所需的线粒体内部膜的梯度生产。有缺陷的C-1是与人类疾病相关的线粒体功能障碍的经常原因。此外生物能衰竭，活性氧（ROS）产生与线粒体功能障碍密切相关。各种研究都暗示了C-I的反向电子转移（RET）是线粒体ROS的主要部位生产。在某些热力学条件下，例如，当向前电子传输（FET）被阻塞时或当琥珀酸酯积聚到高水平时，可能会沿C-I发生RET，从泛氨醇移动电子（COQ10H2）到NAD+，在此过程中产生大量的ROS（RET-ROS）。 ret-Ros已链接到生理过程，例如响应细菌感染的巨噬细胞激活。但是，过度ret- ROS与疾病疾病有关，例如缺血 - 再灌注损伤。 RET的另一个结果是 NAD+转换为NADH，从而减少了NAD+并降低NAD+/NADH比率，该比率已链接到衰老和与年龄有关的疾病。在初步研究中，我们表明，小分子对RET的抑制作用针对NDUFS3的药物，或通过遗传手段部分敲除NDUFS3的药物，可以延长寿命并挽救年龄 - 苍蝇模型中的相关疾病表型。令人兴奋的是，我们的初步研究产生了令人信服的证据 RET的药理抑制可以挽救认知缺陷和神经退行性，并延长 tauopathy鼠标模型。这项研究的目的是使用体内鼠标模型和人IPSC衍生的神经元测试我们的中心假设的模型，即在tauopathy中改变了RET，tau与C-I组件相互作用以影响 RET，NDUFS3的药理或遗传靶向可以恢复RET并提供神经保护作用。尽管压倒性的证据涉及一般的线粒体有缺陷的证据，尤其是C-1，在auopathies中，线粒体和C-I并不是针对auopathies的治疗性发育的重点。积极的结果该项目将有助于验证C-1的RET作为可行的治疗靶标，并刺激开发的利益 RET调节剂作为候选药物，用于治疗tauopathies和其他脑部疾病。