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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：
10012953
负责人：
JANE Y WU
金额：
$ 60.73万
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/10012953
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 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蛋白病是一种神经退行性疾病，其特征是病变组织中存在TDP-43阳性包涵体。阿尔茨海默病(AD)是最常见的痴呆症，临床特征是认知障碍伴记忆丧失，病理上表现为β-淀粉样斑块(Abeta)、tau神经原纤维缠结(Tau NFTs)和神经退行性变。大约50%的AD患者样本除了Abeta和tau NFT外，还有TDP-43阳性病理。此外，TDP-43阳性的AD患者出现包括痴呆症在内的认知障碍的可能性是TDP-43阴性患者的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的发病机制的理解。线粒体功能障碍是阿尔茨海默病的发病机制之一。然而，直到最近才证明，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相关痴呆的治疗开发提供了一条新的途径。尽管已有研究报道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，尤其是与认知功能障碍密切相关的事件，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振奋的初步数据，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，而且也是患者样本的一个显著特征。我们的数据表明，TDP-43诱导线粒体损伤，破坏线粒体蛋白稳定，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、生化和细胞生物学方法，结合动物模型、患者样本和患者IPSC来源的神经元，研究线粒体，特别是丝裂原蛋白水解酶和其他MQC基因在TDP-43诱导的神经退行性变中的作用。在目标1中，我们将确定TDP-43在体内破坏有丝分裂蛋白稳定和诱导UPRmt的作用，并将在培养和体内鉴定对清除错误折叠的TDP-43蛋白至关重要的有丝分裂蛋白酶。在目标2中，我们将通过研究TDP-43与丝裂原蛋白水解酶的相互作用、氧化应激对TDP-43蛋白错误折叠/降解的影响以及候选丝裂原蛋白水解酶在调节MQC中的作用来剖析TDP-43在线粒体中的降解以及TDP-43诱导的神经变性的机制。在目标3中，我们将系统地检测患者样本中的线粒体损伤，并利用患者的IPSC来源的神经元来确定MQC基因在TDP-43蛋白病发病机制中的作用。如果线粒体蛋白平衡的增强和MQC改善TDP-43诱导的人类神经元线粒体损伤和神经退变，将建立一个先前未知的有丝分裂蛋白在TDP-43相关神经退变中的作用。我们拟议工作的完成将有助于阐明AD、AD相关痴呆和其他与TDP-43病理相关的疾病的分子机制。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。