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

项目总结 核膜是包裹基因组的脂类双层，为基因组之间提供物理边界。 细胞质和核质。而原子核通常被描绘成一个被光滑的 核膜的表面，光滑的外部可被核的管状凹陷打断 进入核子内部深处的信封。这种结构被称为“核质网”。增加了 核膜内陷的频率发生在各种疾病状态中，包括各种癌症、病毒感染、 以及椎板病症，这是一组由于编码板层蛋白的基因突变而引起的异质性疾病 A(LMNA)。人类阿尔茨海默病核膜内陷频率显著增加 阿尔茨海默病(AD)脑部疾病最近有报道。核膜内陷是由致病性tau引起的， 阿尔茨海默病的两大病理特征之一。牛磺酸致病性层粘连蛋白功能障碍 核骨架驱动核膜内陷并导致神经元死亡，证明了Lamin 功能障碍会在成年人的大脑中产生严重的影响。这些研究表明，保持适当的核 结构对成年神经元的生存和功能非常重要。我们的初步研究表明，tau- 诱导核膜内陷导致RNA输出有毒增加，并且RNA质量控制是 在紧张症上妥协了。拟议中的实验验证了tau诱导核反应的总体假设 包膜内陷导致RNA出口有毒增加，使RNA质量控制机制不堪重负。 这个提案的总体目标是1)定义tau诱导的核膜内陷在 RNA输出，2)确定遗传和药物减少抑制RNA输出的机制 Tau诱导的神经毒性，以及3)确定无义介导的RNA转录本是否被有限清除 RNA衰变有助于tau和AGE诱导的神经毒性。我们结合了对果蝇的研究，诱导 AD患者的多潜能干细胞(IPSC)来源的神经元，以及死后人类AD的脑组织 解决因果关系，测试具有功能神经网络的老年动物大脑中的假设，并确定 与人类阿尔茨海默病相关。如果我们的假设是正确的，就会出现一种模型，将Lamin的核骨架， 核膜，以及衰老和肌萎缩侧索硬化症之间中央界面的RNA处理。我们预料到 对核包膜内陷的影响进行多系统调查将产生重大影响 涉及AD以外的核结构破坏、衰老和相关的肌萎缩侧索硬化症的疾病，并可能 引领了基于机制的新型疗法的未来发展。

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.