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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：
9788109
负责人：
JANE Y WU
金额：
$ 61.87万
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/9788109
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyloid beta-Protein Amyotrophic Lateral Sclerosis Animal Model Biochemical Bioenergetics Biological Assay Brain Diseases 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 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 induced pluripotent stem cell 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蛋白病是一种以TDP-43阳性包涵体存在于受累组织为特征的神经退行性疾病。阿尔茨海默病（AD）是最常见的痴呆症形式，其临床特征是认知障碍伴记忆丧失，病理特征是β -淀粉样蛋白斑块（Abeta）、tau神经原纤维缠结（tau nft）和神经变性。大约50%的阿尔茨海默病患者样本除了显示β和tau nft外，还显示TDP-43阳性病理。此外，与TDP-43阴性患者相比，TDP-43阳性AD患者出现包括痴呆在内的认知障碍的可能性要高10倍。因此，阐明TDP-43诱导神经退行性疾病的分子机制将有助于我们对阿尔茨海默病、阿尔茨海默病相关痴呆及相关神经退行性疾病发病机制的理解。线粒体功能障碍与阿尔茨海默病的发病有关。然而，直到最近才有证据表明，增强线粒体蛋白平衡可以减少淀粉样蛋白-β错误折叠和神经毒性，为阿尔茨海默病和ad相关痴呆的治疗发展提供了新的途径。尽管已经发表的研究表明TDP-43部分定位于线粒体并与线粒体功能障碍有关，但线粒体是否保护或促进了TDP-43诱导的神经变性，特别是对认知障碍至关重要的事件，仍未得到解决。因此，有必要进行严格和系统的研究，以确定线粒体在与TDP-43相关的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，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，破坏线粒体蛋白质稳态并激活线粒体未折叠蛋白反应（UPRmt）。重要的是，加强线粒体质量控制（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、生化和细胞生物学的综合方法，结合动物模型、患者样本和患者ipsc来源的神经元，来研究线粒体，特别是有丝分裂蛋白酶和其他MQC基因在tdp -43诱导的神经变性中的作用。在Aim 1中，我们将确定TDP-43在破坏有丝分裂蛋白静止和诱导UPRmt中的体内作用，我们将在培养和体内鉴定和表征对清除错误折叠的TDP-43蛋白至关重要的有丝分裂蛋白酶。在Aim 2中，我们将通过检测TDP-43与有丝分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有丝分裂蛋白酶在调节MQC中的功能，来解剖线粒体中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本中的线粒体损伤，并利用患者ipsc来源的神经元确定MQC基因在TDP-43蛋白病变发病机制中的作用。如果线粒体蛋白平衡和MQC的增强改善了TDP-43诱导的人类神经元线粒体损伤和神经退行性变，它将建立一个以前未知的线粒体蛋白平衡在TDP-43相关神经退行性变中的作用。我们所提出的工作的完成将有助于阐明AD、AD相关痴呆和其他具有TDP-43病理的疾病的分子机制。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果。