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.

项目总结