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
• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' 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

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，其特征是受影响组织中存在 TDP-43 阳性包涵体。阿尔茨海默病 (AD) 是最常见的痴呆症，临床特征为认知障碍并伴有记忆丧失，病理特征为 β-淀粉样蛋白斑 (Abeta)、tau 神经原纤维缠结 (tau NFT) 和神经变性。除了 Abeta 和 tau NFT 之外，大约 50% 的 AD 患者样本还显示 TDP-43 阳性病理。此外，与 TDP-43 阴性病例相比，TDP-43 阳性 AD 病例出现认知障碍（包括痴呆症）的可能性高出 10 倍。因此，阐明 TDP-43 诱导神经退行性疾病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，线粒体功能障碍与 AD 发病机制有关。然而，直到最近才被证明，增强线粒体蛋白质稳态可以减少淀粉样蛋白-β 的错误折叠和神经毒性，为阿尔茨海默氏症和 AD 相关痴呆症的治疗开发提供了新途径。尽管已发表 TDP-43 部分定位于线粒体并与线粒体功能障碍相关，但线粒体是否能预防或促进 TDP-43 诱导的神经退行性变（尤其是对认知障碍至关重要的事件）仍悬而未决。因此，有必要进行严格和系统的研究来明确线粒体在与 TDP-43 相关的神经变性中的作用和潜在机制。我们获得了令人兴奋的初步数据，表明线粒体损伤不仅是 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显着特征。我们的数据显示，TDP-43 会诱导线粒体损伤，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，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。我们建议采取综合方法，利用分子、生化和细胞生物学检测以及动物模型、患者样本和患者 iPSC 衍生的神经元来检查线粒体，特别是线粒体蛋白酶和其他 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 在破坏线粒体蛋白质稳态和诱导 UPRmt 方面的体内作用，并且我们将鉴定和表征对于培养物和体内清除错误折叠的 TDP-43 蛋白至关重要的线粒体蛋白酶。在目标 2 中，我们将通过检查 TDP-43 与线粒体蛋白酶的相互作用、氧化应激对 TDP-43 蛋白错误折叠/降解的影响以及候选线粒体蛋白酶在调节 MQC 中的功能，剖析线粒体中 TDP-43 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本中的线粒体损伤，并使用患者 iPSC 衍生的神经元确定 MQC 基因在 TDP-43 蛋白病发病机制中的作用。如果线粒体蛋白质稳态和 MQC 的增强能够改善 TDP-43 诱导的人类神经元线粒体损伤和神经变性，那么将建立线粒体蛋白质稳态在 TDP-43 相关神经变性中以前未知的作用。完成我们提出的工作将有助于阐明 AD、AD 相关痴呆和其他 TDP-43 病理学疾病的分子机制。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。