The Role of Mitochondria in TDP-43 Proteinopathy

线粒体在 TDP-43 蛋白病中的作用

基本信息

  • 批准号:
    10263156
  • 负责人:
  • 金额:
    $ 59.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-30 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

TDP-43 proteinopathy is a spectrum of neurodegenerative diseases characterized by the presence of TDP-43 positive inclusion bodies in the affected tissues. Alzheimer’s disease (AD), the most common form of dementia, is characterized clinically by cognitive impairment with memory loss and pathologically by beta-Amyloid plaques (Abeta), tau neurofibrillary tangles (tau NFTs) and neurodegeneration. Approximately 50% of AD patient samples show TDP-43 positive pathology in addition to Abeta and tau NFTs. Furthermore, TDP-43 positive AD cases are 10 times more likely to show cognitive impairment, including dementia, compared to TDP-43 negative ones. Therefore, elucidating molecular mechanisms underlying TDP-43 induced neurodegeneraion will advance our understanding of the pathogenesis of AD, AD-related dementias, and related neurodegenerative diseases. It is well established that mitochondrial dysfunction contributes to AD pathogenesis. However, only recently has it been demonstrated that enhancing mitochondrial proteostasis reduces amyloid-β misfolding and neurotoxicity, providing a new avenue for therapeutic development in Alzheimer’s and AD-related dementias. Although it has been published that TDP-43 is partially localized in mitochondria and is associated with mitochondrial dysfunction, it remains unresolved whether mitochondria protect against or contribute to TDP-43 induced neurodegeneration, especially events critical for cognitive impairment. Thus, rigorous and systematic studies are necessary to define the role and underlying mechanisms of mitochondria in neurodegeneration associated with TDP-43. We have obtained exciting preliminary data that mitochondrial damage is not only the earliest detectable defect in cellular and animal models of TDP-43 proteinopathy but also a prominent feature in patient samples. Our data show that TDP-43 induces mitochondrial damage, disrupts mitochondrial proteostasis and activates the mitochondrial unfolded protein response (UPRmt). Importantly, enhancing mitochondrial quality control (MQC) not only reduces mitochondrial impairment, but also ameliorates TDP-43-induced neurodegeneration. We propose to take an integrated approach using molecular, biochemical and cell biological assays together with animal models, patient samples and patient iPSC-derived neurons to examine the role of mitochondria, especially mitoproteases and other MQC genes, in TDP-43-induced neurodegeneration. In Aim 1, we will determine the in vivo role of TDP-43 in disrupting mitoproteostasis and inducing UPRmt, and we will identify and characterize mitoproteases critical for clearance of misfolded TDP-43 protein in cultures and in vivo. In Aim 2, we will dissect mechanisms of TDP-43 degradation in mitochondria and TDP-43-induced neurodegeneration by examining interaction of TDP-43 with mitoproteases, impact of oxidative stress on TDP-43 protein misfolding/degradation and the function of the candidate mitoproteases in modulating MQC. In Aim 3, we will systematically examine mitochondrial impairment in patient samples and determine the role of MQC genes in the pathogenesis of TDP-43 proteinopathy using patient iPSC-derived neurons. If enhancement of mitochondrial proteostasis and MQC ameliorates TDP-43 induced mitochondrial damage and neurodegeneration in human neurons, it will establish a previously unknown role of mitoproteostasis in TDP-43 related neurodegeneration. Completion of our proposed work will help elucidate molecular mechanisms underlying AD, AD-related dementias and other disorders with TDP-43 pathology. This study will also identify potential therapeutic targets to improve clinical outcomes of these devastating neurodegenerative diseases.
TDP-43蛋白病是一系列神经退行性疾病,其特征在于在受影响的组织中存在TDP-43阳性包涵体。阿尔茨海默病(AD)是最常见的痴呆形式,其临床特征在于认知障碍伴记忆丧失,病理特征在于β-淀粉样蛋白斑块(Abeta)、tau神经元缠结(tau NFT)和神经变性。大约50%的AD患者样品显示除了Abeta和tau NFT之外的TDP-43阳性病理学。此外,TDP-43阳性AD病例显示认知障碍(包括痴呆)的可能性是TDP-43阴性AD病例的10倍。因此,阐明TDP-43诱导神经退行性变的分子机制将促进我们对AD、AD相关痴呆和相关神经退行性疾病发病机制的理解。众所周知,线粒体功能障碍有助于AD的发病机制。然而,直到最近才证明,增强线粒体蛋白质稳态减少淀粉样蛋白-β错误折叠和神经毒性,为阿尔茨海默氏症和AD相关痴呆的治疗开发提供了新的途径。尽管已经发表了TDP-43部分定位于线粒体中并与线粒体功能障碍相关,但线粒体是否保护或促进TDP-43诱导的神经变性,特别是对认知障碍至关重要的事件,仍然没有解决。因此,有必要进行严格和系统的研究,以确定线粒体在TDP-43相关神经退行性变中的作用和潜在机制。我们已经获得了令人兴奋的初步数据,即线粒体损伤不仅是TDP-43蛋白病细胞和动物模型中最早可检测到的缺陷,而且也是患者样本中的一个突出特征。我们的数据表明,TDP-43诱导线粒体损伤,破坏线粒体蛋白稳态,激活线粒体未折叠蛋白反应(UPRmt)。重要的是,增强线粒体质量控制(MQC)不仅可以减少线粒体损伤,还可以改善TDP-43诱导的神经变性。我们建议采用分子、生物化学和细胞生物学测定的综合方法,结合动物模型、患者样本和患者iPSC衍生的神经元,研究线粒体,特别是丝裂蛋白酶和其他MQC基因在TDP-43诱导的神经变性中的作用。在目标1中,我们将确定TDP-43在体内破坏有丝分裂蛋白稳态和诱导UPRmt的作用,我们将鉴定和表征在培养物和体内清除错误折叠的TDP-43蛋白的关键有丝分裂蛋白酶。在目标2中,我们将通过检查TDP-43与丝裂蛋白酶的相互作用、氧化应激对TDP-43蛋白错误折叠/降解的影响以及候选丝裂蛋白酶在调节MQC中的功能来剖析TDP-43在线粒体中的降解和TDP-43诱导的神经变性的机制。在目标3中,我们将系统地检查患者样品中的线粒体损伤,并使用患者iPSC衍生的神经元确定MQC基因在TDP-43蛋白质病发病机制中的作用。如果线粒体蛋白酶抑制和MQC的增强改善了TDP-43诱导的人类神经元中的线粒体损伤和神经变性,则将确立线粒体蛋白酶抑制在TDP-43相关的神经变性中的先前未知的作用。完成我们的工作将有助于阐明AD,AD相关痴呆和其他疾病的TDP-43病理的分子机制。这项研究还将确定潜在的治疗靶点,以改善这些破坏性神经退行性疾病的临床结局。

项目成果

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JANE Y WU其他文献

JANE Y WU的其他文献

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{{ truncateString('JANE Y WU', 18)}}的其他基金

The Role of Mitochondria in TDP-43 Proteinopathy
线粒体在 TDP-43 蛋白病中的作用
  • 批准号:
    9788109
  • 财政年份:
    2018
  • 资助金额:
    $ 59.4万
  • 项目类别:
The Role of Mitochondria in TDP-43 Proteinopathy
线粒体在 TDP-43 蛋白病中的作用
  • 批准号:
    10458007
  • 财政年份:
    2018
  • 资助金额:
    $ 59.4万
  • 项目类别:
The Role of Mitochondria in TDP-43 Proteinopathy
线粒体在 TDP-43 蛋白病中的作用
  • 批准号:
    10012953
  • 财政年份:
    2018
  • 资助金额:
    $ 59.4万
  • 项目类别:
The role of deubiquitinating enzyme USP33 in Slit-Robo signaling in lung cancer
去泛素化酶 USP33 在肺癌 Slit-Robo 信号传导中的作用
  • 批准号:
    8632559
  • 财政年份:
    2014
  • 资助金额:
    $ 59.4万
  • 项目类别:
The role of deubiquitinating enzyme USP33 in Slit-Robo signaling in lung cancer
去泛素化酶 USP33 在肺癌 Slit-Robo 信号传导中的作用
  • 批准号:
    8819521
  • 财政年份:
    2014
  • 资助金额:
    $ 59.4万
  • 项目类别:
The role of deubiquitinating enzyme USP33 in Slit-Robo signaling in lung cancer
去泛素化酶 USP33 在肺癌 Slit-Robo 信号传导中的作用
  • 批准号:
    9232089
  • 财政年份:
    2014
  • 资助金额:
    $ 59.4万
  • 项目类别:
Mechanisms regulating tau alternative pre-mRNA splicing
tau 选择性前 mRNA 剪接的调节机制
  • 批准号:
    8311629
  • 财政年份:
    2011
  • 资助金额:
    $ 59.4万
  • 项目类别:
Mechanisms regulating tau alternative pre-mRNA splicing
tau 选择性前 mRNA 剪接的调节机制
  • 批准号:
    8508774
  • 财政年份:
    2011
  • 资助金额:
    $ 59.4万
  • 项目类别:
Mechanisms regulating tau alternative pre-mRNA splicing
tau 选择性前 mRNA 剪接的调节机制
  • 批准号:
    8726259
  • 财政年份:
    2011
  • 资助金额:
    $ 59.4万
  • 项目类别:
Mechanisms regulating tau alternative pre-mRNA splicing
tau 选择性前 mRNA 剪接的调节机制
  • 批准号:
    8116362
  • 财政年份:
    2011
  • 资助金额:
    $ 59.4万
  • 项目类别:
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