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：
10458007
负责人：
JANE Y WU
金额：
$ 58.21万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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

来源：
https://reporter.nih.gov/project-details/10458007
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid beta-Protein Amyotrophic Lateral Sclerosis Animal Model Biochemical Bioenergetics Biological Assay Cell Death Cell model Cells Clinical Cultured Cells Data Defect Dementia Disease Disease Progression Event Failure Frontotemporal Lobar Degenerations Future Gene Expression Gene Mutation Genes Goals Human Impaired cognition Impairment Inclusion Bodies Induced pluripotent stem cell derived neurons Investigation Lead Mediating Memory Loss Mitochondria Molecular Morphology Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Protein Outcome Oxidative Stress PINK1 gene Pathogenesis Pathogenicity Pathologic Pathology Patients Peptide Hydrolases Play Proteins Publishing Quality Control RNA-Binding Proteins Reporting Role Sampling Senile Plaques Solid Testing Time Tissues Transgenic Mice Transgenic Organisms Work base cytotoxic cytotoxicity fly improved in vivo innovation mitochondrial dysfunction mutant neurotoxicity protein TDP-43 protein misfolding proteostasis response tau Proteins tau aggregation therapeutic development therapeutic target

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蛋白质病是一系列神经退行性疾病，其特征是受影响组织中TDP-43阳性包含体。阿尔茨海默氏病（AD）是痴呆症的最常见形式，在临床上是由认知障碍和记忆力丧失和病理学上的特征，并由β-淀粉样蛋白斑块（ABETA），TAU神经原纤维缠结（TAU NFTS）和NeuroDegeneration在病理上表征。除了Abeta和Tau NFT之外，大约50％的AD患者样品显示出TDP-43阳性病理。此外，与TDP-43阴性相比，TDP-43阳性AD阳性病例表现出认知障碍的可能性高10倍。因此，阐明TDP-43诱导的神经变性基础的分子机制将提高我们对AD，与AD相关痴呆症和相关神经退行性疾病的发病机理的理解。很好地确定线粒体功能障碍会导致AD发病机理。然而，直到最近才证明，增强线粒体蛋白抑制作用会减少淀粉样蛋白β的错误折叠和神经毒性，从而为阿尔茨海默氏症和与广告相关的痴呆症提供了新的热发展途径。尽管已经发表了TDP-43部分定位在线粒体中，并且与线粒体功能障碍有关，但无论是线粒体防止还是有助于TDP-43诱导的神经变性，尤其是对认知障碍至关重要的事件，它仍然无法解决。这对于定义与TDP-43相关的神经变性中线粒体的作用和潜在机制是必要的，并且需要进行严格的系统研究。我们获得了令人兴奋的初步数据，即线粒体损伤不仅是TDP-43蛋白质病细胞和动物模型中最早可检测到的缺陷，而且是患者样品中的重要特征。我们的数据表明，TDP-43诱导线粒体损伤，破坏线粒体蛋白抑制并激活线粒体展开的蛋白质反应（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害，而且还可以改善TDP-43诱导的神经变性。我们建议使用分子，生化和细胞生物学测定，以及动物模型，患者样品和患者IPSC衍生的神经元进行综合方法，以检查TDP-43诱导的神经变性的线粒体，尤其是Mitoproteases和其他MQC基因的作用。在AIM 1中，我们将确定TDP-43在破坏Mitroteototasis和诱导UPRMT的体内作用，并且我们将识别和表征对清除培养物和体内中含有错误折叠的TDP-43蛋白的至关重要的电螺旋a是至关重要的。在AIM 2中，我们将通过检查TDP-43与水核酸蛋白酶的相互作用，氧化应激对TDP-43蛋白质降解/脱位和候选物的功能中的氧化应激对TDP-43蛋白质降解/脱位的影响，从而解剖TDP-43降解和TDP-43诱导的神经变性的机制。在AIM 3中，我们将系统地检查患者样品中的线粒体损伤，并确定MQC基因使用患者IPSC衍生的神经元在TDP-43蛋白质病发病中的作用。如果增强线粒体蛋白抑制剂和MQC会改善TDP-43在人神经元中诱导的线粒体损伤和神经变性，则它将在TDP-43相关的神经变性世代中建立以前未知的mitopotototasis的作用。我们提出的工作的完成将有助于阐明AD基础的分子机制，与AD相关的痴呆症和其他具有TDP-43病理学的疾病。这项研究还将确定潜在的治疗靶标，以改善这些毁灭性神经退行性疾病的临床结果。