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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

基本信息

批准号：
10532781
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532781
关键词：
Activities of Daily Living Address Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient 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 Lipid Bilayers Malignant Neoplasms Mechanical Stress Mediating Mediator Modeling Mutation Neurodegenerative Disorders Neurologic Dysfunctions Neuronal Dysfunction Neurons Nuclear Nuclear Envelope Nuclear Pore Nucleoplasm Pathologic Pathway interactions Peptides Phenotype Physiological Poly(A)+ RNA Polyadenylation Premature aging syndrome Production Progeria Prosencephalon Proteins Quality Control RNA RNA Decay Reporting Research Reticulum Risk Factors Role Sampling Structure Surface Syndrome System Tauopathies Testing Therapeutic Intervention Transcript Transgenic Organisms Tubular formation Virus Diseases Visualization age related aged aging brain brain tissue cell type experimental study induced pluripotent stem cell model organism neuron loss neurotoxicity new therapeutic target novel novel therapeutic intervention optogenetics pharmacologic programs response tau Proteins tau mutation

项目摘要

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.

项目概要核膜是一个脂质双层，包裹着基因组，并在基因组之间提供了物理边界。细胞质和核质。虽然原子核通常被描绘成一个被光滑物体包围的球体核膜表面，光滑的外部可以被核的管状内陷打断包络进入核内部深处。这种结构被称为“核质网”。增加核膜内陷的频率发生在疾病状态下，包括各种癌症、病毒感染、和核纤层蛋白病，一组由于编码核纤层蛋白的基因突变而引起的异质性疾病 A（LMNA）。人类阿尔茨海默病患者核膜内陷频率显着增加最近有报道称脑部疾病（AD）。核膜内陷是由致病性 tau 蛋白引起的， AD 的两大病理特征之一。致病性 tau 诱导的核纤层蛋白功能障碍核骨架驱动核膜内陷并导致神经元死亡，证明核纤层蛋白功能障碍会对成人大脑产生严重影响。这些研究表明，维持适当的核结构对于成年神经元的生存和功能很重要。我们的初步研究表明 tau- 诱导的核膜内陷会导致 RNA 输出毒性增加，并且 RNA 质量控制是 tau蛋白病受到损害。所提出的实验检验了 tau 诱导核的总体假设包膜内陷会导致 RNA 输出有毒增加，从而压垮 RNA 质量控制机制。该提案的总体目标是 1) 定义 tau 诱导的核膜内陷对 RNA 输出，2) 确定 RNA 输出的遗传和药理减少抑制的机制 tau 诱导的神经毒性，以及 3) 确定无义介导的 RNA 转录物清除是否有限 RNA 衰变会导致 tau 蛋白和年龄引起的神经毒性。我们结合果蝇的研究，诱导来自 AD 患者的多能干细胞 (iPSC) 衍生的神经元以及死后的人类 AD 脑组织解决因果关系，测试具有功能神经元网络的老年动物大脑中的假设，并确定与人类 AD 的相关性。如果我们的假设是正确的，就会出现一个模型，将核纤层蛋白核骨架，核膜，以及衰老和 tau 蛋白病之间中心界面的 RNA 处理。我们预计对核膜内陷影响的多系统调查将产生重大影响涉及 AD 之外的核结构破坏、衰老和相关 tau蛋白病的疾病，并且可以导致未来新型基于机制的疗法的发展。