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:
  • 金额:
    $ 19.36万
  • 依托单位:
  • 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

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.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Bingwei Lu其他文献

Bingwei Lu的其他文献

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{{ truncateString('Bingwei Lu', 18)}}的其他基金

A Novel Role of Fragile-X Mental Retardation Protein in Mitochondrial Calcium Homeostasis
Fragile-X 智力迟钝蛋白在线粒体钙稳态中的新作用
  • 批准号:
    10452354
  • 财政年份:
    2022
  • 资助金额:
    $ 19.36万
  • 项目类别:
A Novel Role of Fragile-X Mental Retardation Protein in Mitochondrial Calcium Homeostasis
Fragile-X 智力迟钝蛋白在线粒体钙稳态中的新作用
  • 批准号:
    10612482
  • 财政年份:
    2022
  • 资助金额:
    $ 19.36万
  • 项目类别:
Interplay between amyloid precursor protein metabolism and ER-mitochondria contact
淀粉样蛋白前体蛋白代谢与内质网线粒体接触之间的相互作用
  • 批准号:
    10301076
  • 财政年份:
    2021
  • 资助金额:
    $ 19.36万
  • 项目类别:
Interplay between amyloid precursor protein metabolism and ER-mitochondria contact
淀粉样蛋白前体蛋白代谢与内质网线粒体接触之间的相互作用
  • 批准号:
    10470218
  • 财政年份:
    2021
  • 资助金额:
    $ 19.36万
  • 项目类别:
Understanding SHRF, an RNA exosome-linked disease with multi-organ involvement
了解 SHRF,一种与 RNA 外泌体相关的多器官受累疾病
  • 批准号:
    10305689
  • 财政年份:
    2020
  • 资助金额:
    $ 19.36万
  • 项目类别:
Mitochondrial inner membrane architecture in skeletal muscle pathophysiology
骨骼肌病理生理学中的线粒体内膜结构
  • 批准号:
    10317296
  • 财政年份:
    2020
  • 资助金额:
    $ 19.36万
  • 项目类别:
Mitochondrial inner membrane architecture in skeletal muscle pathophysiology
骨骼肌病理生理学中的线粒体内膜结构
  • 批准号:
    10441283
  • 财政年份:
    2019
  • 资助金额:
    $ 19.36万
  • 项目类别:
Mitochondrial inner membrane architecture in skeletal muscle pathophysiology
骨骼肌病理生理学中的线粒体内膜结构
  • 批准号:
    9979767
  • 财政年份:
    2019
  • 资助金额:
    $ 19.36万
  • 项目类别:
Mitochondrial inner membrane architecture in skeletal muscle pathophysiology
骨骼肌病理生理学中的线粒体内膜结构
  • 批准号:
    10657388
  • 财政年份:
    2019
  • 资助金额:
    $ 19.36万
  • 项目类别:
Mitochondrial inner membrane architecture in skeletal muscle pathophysiology
骨骼肌病理生理学中的线粒体内膜结构
  • 批准号:
    10208725
  • 财政年份:
    2019
  • 资助金额:
    $ 19.36万
  • 项目类别:

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