Mechanisms underlying Tip60 HAT action in neuroprotection of cognitive function

摘要 阿尔茨海默病(AD)是一种衰弱的进行性神经退行性疾病(ND)，其特点是 最初的轻度认知障碍(MCI)，随后是痴呆症。AD进展的严重程度取决于 遗传、年龄和环境因素之间的复杂相互作用在很大程度上是由表观遗传协调的 组蛋白乙酰化(HA)介导的基因调控机制。大脑中HA的动态平衡是由 拮抗组蛋白乙酰转移酶(HAT)和组蛋白脱乙酰基转移酶(HDAC) 和擦除认知相关的组蛋白乙酰化标记。大脑中HA水平的降低会导致 神经元染色质包装的改变，伴随着转录失调，这是一个关键的初始步骤 在阿尔茨海默病病因学。然而，产生这些不同的神经表观基因组乙酰化的特定HAT 信号在大脑中，因此作为潜在的记忆损害阿尔茨海默病HA改变的致病因素， 在很大程度上仍然不为人知。我们实验室长期以来一直对HAT Tip60作为表观遗传介体感兴趣 认知和阿尔茨海默病中神经转录调节反应的研究。我们开发了一款功能强大的应用程序：Tip60 Drophila 使我们能够在AD淀粉样蛋白作用下调节神经回路中Tip60 HAT水平的模型系统 前体蛋白(APP)神经退行性疾病，体内。它的使用导致了一份已发表研究的概要 这确立了Tip60 HAT介导的染色质动力学在认知功能和 阿尔茨海默病的神经保护。在这一资助期间，我们还取得了几项独立和惊人的发现 关于Tip60在介导神经元基因控制中的替代新细胞机制 广告。其中包括：(1)经验依赖(ED)Tip60核质转运(NCT)和(2)一种新的 Tip60的RNA结合功能。这项提案的首要目标是阐明这些新的Tip60功能， 以及产生新颖的Tip60特异性治疗化合物，加深我们对Tip60‘S独有的认识 神经系统生物学和阿尔茨海默病神经保护的作用。为了实现这一研究目标，我们团队结合了 在Tip60在认知和AD方面的独特但互补的领域的专业知识(大象，PI)， RNA剪接中的神经表观遗传学(Heller，COI)和新药发现(Kortegare，COI)提出以下建议 具体目标：在目标1中，我们从功能上评估神经元体验中的Tip60核浆转运(NCT)- 依赖基因控制。在目标2中，我们剖析了Tip60染色质上的一个新的双水平神经元功能和 †-HE脑内的核糖核酸剪接水平。在目标3中，我们将产生新的基于Tip60的治疗化合物来识别 药理增强人Tip60‘S帽子活性的认知益处。成功完成这项工作 该项目将发现治疗AD的新分子途径、靶点和早期生物标记物，并产生特异的 具有AD神经保护功能的Tip60 HAT激活剂化合物。

ABSTRACT Alzheimer’s disease (AD) is a debilitating progressive neurodegenerative disorder (ND) hallmarked by initial mild cognitive impairment (MCI) followed by dementia. The severity of AD progression is dependent upon the complex interplay between genetics, age, and environmental factors orchestrated in large part, by epigenetic histone acetylation (HA) mediated gene regulatory mechanisms. HA homoeostasis in the brain is maintained by antagonizing histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) enzymes that generate and erase cognition-linked histone acetylation marks, respectively. Reduced HA levels in the brain cause chromatin packaging alterations in neurons, with concomitant transcriptional dysregulation that is a key initial step in AD etiology. Nevertheless, the specific HATs that generate these distinct neuroepigenomic acetylation signatures in the brain, and thus serve as causative agents underlying memory impairing HA alterations in AD, remain largely unknown. Our laboratory has a long-standing interest in the HAT Tip60 as an epigenetic mediator of neural transcriptional regulatory responses in cognition and AD. We generated a robust APP;Tip60 Drosophila model system that enables us to modulate Tip60 HAT levels in neural circuits of choice under AD amyloid precursor protein (APP) neurodegenerative conditions, in vivo. Its use led to a compendium of published studies that establish a central role for Tip60 HAT mediated chromatin dynamics in cognitive function and neuroprotection in AD. During this funding period, we also made several separate and striking discoveries regarding alternative novel cellular mechanisms for Tip60 in mediating neuronal gene control that are disrupted in AD. These include: (1) experience-dependent (ED) Tip60 nucleocytoplasmic transport (NCT) and (2) a novel RNA-binding function for Tip60. The overarching goal of this proposal is to elucidate these new Tip60 functions, as well as generate novel Tip60 specific therapeutic compounds, to deepen our understanding of Tip60’s unique roles in nervous system biology and AD neuroprotection. To achieve this research goal, our team combines expertise in the unique but complementing areas of Tip60 function in cognition and AD (Elefant, PI), neuroepigenetics in RNA splicing (Heller, CoI) and novel drug discovery (Kortegare, CoI) to propose the following specific aims: In Aim 1 we functionally assess Tip60 nucleocytoplasmic transport (NCT) in neuronal experience- dependent gene control. In Aim 2 we dissect a novel bi-level neuronal function for Tip60 at the chromatin and RNA splicing level in †he brain. In Aim 3 we will generate novel Tip60 based therapeutic compounds to identify cognitive benefits of pharmacologically enhancing human Tip60’s HAT activity. Successful completion of this project will uncover novel molecular pathways, targets and early biomarkers to treat AD and generate a specific Tip60 HAT activator compound with AD neuroprotection capabilities.