Dysregulation of Protein Prenylation in the Pathogenesis of Alzheimer's Disease

项目摘要 阿尔茨海默病（AD）发展的致病机制仍然难以捉摸。 有趣的是，新出现的证据表明，蛋白质的翻译后脂质修饰，称为 异戊烯化可能在AD的发病机制中起重要作用。异戊二烯化反应由以下物质催化： 异戊烯基转移酶，其将类异戊二烯（法呢基或香叶基香叶基焦磷酸）连接到具有 特征性C-末端基序。脂质异戊二烯基促进蛋白质在细胞膜中的锚定， 介导蛋白质-蛋白质相互作用。异戊烯化蛋白，包括包含Ras的小GTP酶 超家族沿着异源三聚体G蛋白，参与调节多种细胞过程。在AD中， 蛋白质异戊烯化的作用还未被充分研究。一些研究表明，蛋白质异戊二烯化的调节 影响淀粉样蛋白-β（Aβ）和tau水平、神经炎症、突触可塑性和认知功能。 然而，这些研究大多数是在体外进行的，并通过药理学抑制类异戊二烯 产生而不是直接调节蛋白质异戊二烯化。使用直接遗传方法，我们最近的 研究表明，这两种蛋白质异戊二烯化途径发挥不同的神经生理作用。降低蛋白质 法尼基化可挽救认知功能并减弱Aβ病理，同时减少蛋白质 香叶基香叶基化对突触功能产生不利影响。另外，我们的初步研究显示 膜相关H-Ras（一种专门的法尼基化蛋白）的水平在 轻度认知障碍（MCI）和AD患者的大脑与正常人相比， 认知功能;法尼基化的H-Ras水平与ERK的激活显著相关， H-Ras的主要下游效应子。因此，我们假设蛋白质法尼基化的上调是一种 在AD的致病级联和下游信号传导激活中具有首要重要性的早期事件 这些通路有助于认知障碍和神经病理学的发展。这个核心假设 将通过三个特定目标进行严格测试，结合创新的遗传、行为、 电生理学和异戊二烯组学方法。目的1是验证神经元特异性缺失 蛋白质法尼基化减轻认知缺陷，突触功能障碍，和病理学在小鼠模型中， AD.目的2是验证H-Ras缺失改善而H-Ras过度激活的假设 加重AD小鼠的认知/突触缺陷和病理学。目的3是阐明 AD病理学和小鼠模型和人脑组织中异戊二烯化蛋白的水平。总目标 该项目的目的是揭示AD的未充分研究但潜在的关键致病机制， 蛋白质异戊二烯化和相关途径。澄清异戊烯化和AD之间的联系可能是一个 变革性的发现，并导致新的治疗策略的发展。

PROJECT SUMMARY The pathogenic mechanisms underlying the development of Alzheimer’s disease (AD) remain elusive. Intriguingly, emerging evidence indicates that a posttranslational lipid modification of proteins, known as prenylation, may play an important role in the pathogenesis of AD. Prenylation reactions are catalyzed by prenyltransferases that attach isoprenoids, either farnesyl or geranylgeranyl pyrophosphate, to proteins with a characteristic C-terminal motif. The lipid prenyl group facilitates anchoring of proteins in cell membranes and mediates protein-protein interactions. Prenylated proteins, including small GTPases comprising the Ras superfamily along with heterotrimeric G-proteins, are involved in regulating diverse cellular processes. In AD, the role of protein prenylation is underexplored. Several studies show that modulation of protein prenylation influences amyloid-β (Aβ) and tau levels, neuroinflammation, synaptic plasticity, and cognitive function. However, most of those studies were conducted in vitro and by pharmacological inhibition of isoprenoid production rather than direct modulation of protein prenylation. Using a direct genetic approach, our recent studies show that the two protein prenylation pathways play distinct neurophysiological roles. Reducing protein farnesylation rescues cognitive function as well as attenuates Aβ pathology whereas reducing protein geranylgeranylation results in adverse effects on synaptic function. In addition, our preliminary studies show that the level of membrane-associated H-Ras, an exclusively farnesylated protein, is significantly increased in the brain of patients with mild cognitive impairment (MCI) and AD compared to individuals with normal cognitive function; and the level of farnesylated H-Ras correlates significantly with the activation of ERK, a major downstream effector of H-Ras. Thus, we hypothesize that upregulation of protein farnesylation is an early event with primary importance in the pathogenic cascade of AD and activation of downstream signaling pathways contributes to the development of cognitive impairment and neuropathology. This central hypothesis will be tested rigorously by three specific aims using a combination of innovative genetic, behavioral, electrophysiological, and prenylomic approaches. Aim 1 is to test the hypothesis that neuron-specific deletion of protein farnesylation mitigates cognitive deficit, synaptic dysfunction, and pathology in a mouse model of AD. Aim 2 is to test the hypothesis that deletion of H-Ras improves whereas over-activation of H-Ras exacerbates cognitive/synaptic deficit and pathology in AD mice. Aim 3 is to elucidate the relationship between AD pathology and the levels of prenylated proteins in mouse models and human brain tissues. The overall goal of the project is to unravel the underexplored but potentially critical pathogenic mechanisms of AD involving protein prenylation and related pathways. Clarifying the linkage between prenylation and AD could be a transformative discovery and lead to the development of new therapeutic strategies.