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

项目摘要 核被膜是一个脂质双层，包裹着基因组，并提供了基因组之间的物理边界 细胞质和核质。虽然原子核通常被描绘成一个被光滑的 在核膜的表面，光滑的外部可以被核膜的管状内陷中断 包裹在核内部深处。这种结构被称为"核质网"。增加 核膜内陷的频率发生在包括各种癌症，病毒感染， 和核纤层蛋白病，一组异质性疾病，由于核纤层蛋白编码基因的突变而引起 A（LMNA）。阿尔茨海默病患者核被膜内陷频率显著增加 脑疾病（AD）的研究最近有报道。核膜内陷由致病性tau蛋白引起， AD的两个主要病理标志之一。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，表明核纤层蛋白 功能障碍对成年人的大脑有严重的影响。这些研究表明，保持适当的核 结构对于成年神经元的存活和功能是重要的。我们的初步研究表明tau- 诱导的核膜内陷导致RNA输出的毒性增加，并且RNA质量控制是 在tau蛋白病中受损。拟议的实验测试了总体假设，即tau诱导的核 包膜内陷导致RNA输出的毒性增加，其破坏了mRNA质量控制机制。 该提案的总体目标是：1）定义tau诱导的核膜内陷在 RNA输出，2）确定遗传和药理学减少RNA输出抑制 tau诱导的神经毒性，以及3）确定无义介导的RNA转录本的清除是否有限 RNA衰变有助于tau蛋白和年龄诱导的神经毒性。我们联合收割机在果蝇中的研究， 来自AD患者的多能干细胞（iPSC）衍生的神经元和死后人AD脑组织， 解决因果关系，在具有功能性神经元网络的老年动物大脑中测试假设，并确定 与人类AD的关系如果我们的假设是正确的，一个模型将会出现， 核被膜，以及衰老和tau蛋白病之间中央界面的RNA处理。我们预计 对核膜内陷影响的多系统研究将产生重大影响 涉及AD以外的核结构破坏、衰老和相关tau蛋白病的疾病， 导致未来开发新的、基于机制的疗法。

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.