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.

项目概要 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 蛋白异常与神经元损失和认知缺陷更好地相关 比淀粉样蛋白负担。人们对开发用于治疗 AD 和其他疾病的 tau 靶向药物越来越感兴趣 tau蛋白病。开发有效的 tau 靶向药物需要对致病因素有更深入、更广泛的了解 tau 的机制。最近的研究揭示了 tau 蛋白与线粒体蛋白的广泛相互作用。有趣的是， 对动物模型和人类的研究发现了 tau 蛋白和线粒体复合物-I (C-I) 之间的特定联系 功能障碍，但具体机制尚不清楚。 C-I是呼吸链最大的多亚基复合体 人体中含有 45 个亚基。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输链 (ETC) 从 NADH 转移到泛醌， 伴随着质子泵浦以产生 ATP 所需的穿过线粒体内膜的梯度 生产。 C-I 缺陷是导致人类疾病相关线粒体功能障碍的常见原因。此外 生物能量衰竭、活性氧（ROS）的产生与线粒体功能障碍密切相关。 各种研究表明 C-I 处的反向电子转移 (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 (CoQ10H2) 中移动电子 转化为 NAD+，在此过程中产生大量 ROS (RET-ROS)。 RET-ROS 已链接至 生理过程，例如响应细菌感染的巨噬细胞激活。然而，过多的RET- ROS 与缺血再灌注损伤等疾病有关。 RET 的另一个结果是 NAD+ 转化为 NADH，从而减少 NAD+ 并降低 NAD+/NADH 比率，这与 衰老和与年龄相关的疾病。在初步研究中，我们已经表明小分子对 RET 的抑制 靶向 NDUFS3 的药物，或通过基因手段部分敲除 NDUFS3，可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 的药理学抑制可以挽救认知缺陷和神经退行性变并延长寿命 tau蛋白病小鼠模型。本研究的目标是使用体内小鼠模型和人类 iPSC 衍生的神经元 模型来测试我们的中心假设，即 RET 在 tau 病中发生改变，tau 与 C-I 成分相互作用以影响 RET，并且 NDUFS3 的药理学或基因靶向可以恢复 RET 并提供神经保护。尽管 压倒性的证据表明线粒体缺陷，特别是 C-I，在 tau蛋白病中， 线粒体和 C-I 尚未成为针对 tau 蛋白病的治疗开发的重点。积极成果 该项目将有助于验证 C-I 的 RET 作为可行的治疗靶点，并激发开发兴趣 RET 调节剂作为治疗 tau 蛋白病和可能的其他脑部疾病的候选药物。