Mechanisms of tau- and aging-induced neurological dysfunction: Focus on the nucleus

tau 蛋白和衰老引起的神经功能障碍的机制：聚焦于细胞核

• 批准号: 10343725
• 负责人: Bess Frost
• 金额: $ 58.37万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343725
• 关键词: Activities of Daily Living; Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Animal Model; Animals; Architecture; Autopsy; Bioinformatics; Biological Process; Brain; Cell Death; Cell Nucleus; Cytoplasm; Deposition; Development; Disease; Drosophila genus; Drosophila melanogaster; Etiology; F-Actin; Frequencies; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Genome; Goals; Human; Induced pluripotent stem cell derived neurons; Intermediate Filaments; Interruption; Investigation; Lamin Type A; Lamins; Lead; Lipid Bilayers; Malignant Neoplasms; Mechanical Stress; Mediating; Mediator of activation protein; Modeling; Mutation; Neurodegenerative Disorders; Neurologic Dysfunctions; Neuronal Dysfunction; Neurons; Nuclear; Nuclear Envelope; Nuclear Pore; Nucleoplasm; Pathologic; Pathway interactions; Peptides; Pharmacology; Phenotype; Physiological; Poly A; Production; Progeria; Prosencephalon; Proteins; Quality Control; RNA; RNA Decay; Reporting; Research; Reticulum; Risk Factors; Role; Sampling; Structure; Surface; Syndrome; Tauopathies; Testing; Therapeutic Intervention; Transcript; Transgenic Organisms; Tubular formation; Viral; Virus Diseases; age related; aged; aging brain; base; brain tissue; cell type; experimental study; induced pluripotent stem cell; neuron loss; neurotoxicity; new therapeutic target; novel; novel therapeutic intervention; optogenetics; premature; programs; response; tau Proteins; tau mutation

PROJECT SUMMARY The nuclear envelope is a lipid bilayer that encases the genome and provides a physical boundary between the cytoplasm and the nucleoplasm. While the nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope, the smooth exterior can be interrupted by tubular invaginations of the nuclear envelope into the deep nuclear interior. Such structures are termed the “nucleoplasmic reticulum.” Increased frequency of nuclear envelope invagination occurs in disease states including various cancers, viral infections, and laminopathies, a group of heterogeneous disorders that arise due to mutations in the gene encoding lamin A (LMNA). A significant increase in the frequency of nuclear envelope invaginations in the human Alzheimer’s disease (AD) brain has recently been reported. Nuclear envelope invaginations are caused by pathogenic tau, one of the two major pathological hallmarks of AD. Pathogenic tau-induced dysfunction of the lamin nucleoskeleton drives nuclear envelope invagination and causes neuronal death, demonstrating that lamin dysfunction has severe repercussions in the adult brain. These studies suggest that maintaining proper nuclear architecture is important for survival and function of adult neurons. Our preliminary studies suggest that tau- induced nuclear envelope invagination causes a toxic increase in RNA export, and that RNA quality control is compromised in tauopathy. The proposed experiments test the overall hypothesis that tau-induced nuclear envelope invaginations cause a toxic increase in RNA export that overwhelms RNA quality control machinery. The overall goals of this proposal are to 1) Define the role of tau-induced nuclear envelope invaginations on RNA export, 2) Identify the mechanism whereby genetic and pharmacologic reduction of RNA export suppress tau-induced neurotoxicity, and 3) Determine if limited clearance of RNA transcripts by nonsense-mediated RNA decay contributes to tau and age-induced neurotoxicity. We combine studies in Drosophila, induced pluripotent stem cell (iPSC)-derived neurons from AD patients, and postmortem human AD brain tissue to address causality, test hypotheses in brains of aged animals with functional neuronal networks, and determine relevance to human AD. If our hypothesis is correct, a model will emerge that puts the lamin nucleoskeleton, nuclear envelope, and RNA handling at the central interface between aging and tauopathy. We anticipate that a multi-system investigation into the repercussions of nuclear envelope invagination will have a major impact on disorders involving nuclear architecture disruption beyond AD, aging and related tauopathies, and could lead to future development of novel, mechanism-based therapies.

项目摘要 核包膜是一种脂质双层，它包围了基因组，并在 细胞质和核质。而核通常被描述为一个被平滑环绕的球体 核包膜的表面，光滑的外部可以被核的管状内幕中断 封底进入深核内部。这种结构称为“核质网”。增加 核包膜的频率发生在包括各种癌症，病毒感染的疾病状态中， 和椎板病，这是一组由于编码层粘连蛋白的突变引起的异质性疾病 A（LMNA）。人类阿尔茨海默氏症中核包膜起伏的频率显着增加 疾病（AD）大脑最近有报道。核包络起伏是由致病性tau引起的 AD的两个主要病理标志之一。致病性tau诱导的层粘连功能障碍 核骨骼驱动核包膜创新并导致神经元死亡，表明层粘连蛋白 功能障碍在成人大脑中产生严重影响。这些研究表明，保持适当的核 建筑对于成人神经元的生存和功能很重要。我们的初步研究表明tau- 诱导的核包膜的内陷导致RNA导出的毒性增加，RNA质量控制是 在tauopathy中受到妥协。提出的实验检验了tau诱导的核的总体假设 包络起伏会导致RNA导出的有毒增加，使RNA质量控制机制不堪重负。 该提案的总体目标是1）定义tau引起的核包络创新在 RNA导出，2）确定RNA导出遗传和药物提取的机制 TAU诱导的神经毒性，3）确定无义介导的RNA转录本是否有限 RNA衰减有助于TAU和年龄引起的神经毒性。我们结合了果蝇的研究，诱导 来自AD患者的多能干细胞（IPSC）衍生的神经元，并在死后人类AD脑组织到 解决因果关系，具有功能性神经元网络的老年动物大脑的检验假设，并确定 与人类广告有关。如果我们的假设是正确的，则会出现一个模型，将层粘连核骨骨骼呈现为 核包膜，以及在衰老和tauopathy之间的中央界面处的RNA处理。我们预料到这一点 对核信封内部影响的影响的多系统调查将产生重大影响 关于涉及广告，衰老和相关tauopath的核建筑中断的疾病，并且可以 导致基于机制的新型疗法的未来发展。