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

阿尔茨海默病发病机制中蛋白质异戊二烯化的失调

基本信息

批准号：
9376111
负责人：
MARK D DISTEFANO
金额：
$ 187.59万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9376111
关键词：
Adverse effects Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Attenuated Behavioral Biochemical Brain Brain Diseases Brain Pathology C-terminal Cell membrane Cell physiology Cerebrum Characteristics Cognition Cognitive Cognitive deficits Data Dementia Development Dimethylallyltranstransferase Disease Elderly Electrophysiology (science)Embryo Event Functional disorder Genetic Genotype Goals HRAS gene Heterotrimeric GTP-Binding Proteins Human Impaired cognition In Vitro Individual Lead Letters Link Lipids LoxP-flanked allele Mediating Membrane Modification Monomeric GTP-Binding Proteins Mus Neurodegenerative Disorders Neurofibrillary Tangles Neurons Pathogenesis Pathogenicity Pathology Pathway interactions Patients Pharmacology Play Positioning Attribute Post-Translational Protein Processing Process Production Protein Dynamics Protein Farnesylation Protein Geranylgeranylation Protein Isoprenylation Proteins Reaction Research Role Senile Plaques Signal Pathway Synapses Synaptic plasticity Testing Up-Regulation abeta accumulation analog base behavior test beta amyloid pathology brain tissue cognitive development cognitive function design effective intervention experience experimental study farnesyl pyrophosphate genetic approach geranylgeranyl pyrophosphate human tissue hyperphosphorylated tau improved innovation isoprenoid mild cognitive impairment mouse Cre recombinase mouse model neuroinflammation neuropathology neurophysiology novel therapeutic intervention prenyl prenylation promoter protein B protein protein interaction synaptic function tau Proteins

项目摘要

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.

项目总结阿尔茨海默病(AD)的发病机制尚不清楚。有趣的是，新出现的证据表明，蛋白质的翻译后脂质修饰，即前烯基化可能在AD的发病机制中起重要作用。预加成反应的催化条件是异戊二烯转移酶，将异戊二烯类物质，法尼基或香叶基焦磷酸，连接到具有特有的C-末端基序。脂基戊烯基团有助于蛋白质在细胞膜上的锚定和调节蛋白质与蛋白质的相互作用。预基化蛋白，包括组成RAS的小GTP酶超家族和异三聚体G蛋白一起参与调节不同的细胞过程。在公元后，蛋白质预烯基化的作用还没有得到充分的研究。多项研究表明，蛋白质预烯基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，这些研究大多是在体外进行的，并通过药物抑制类异戊二烯进行。产生而不是直接调节蛋白质的戊二烯基化。使用直接遗传方法，我们最近研究表明，这两条蛋白质预烯基化途径发挥着不同的神经生理作用。还原蛋白质法尼化既可挽救认知功能，又可减轻β的病理，而降低蛋白质 Geranylgeranyation对突触功能有不良影响。此外，我们的初步研究表明，膜相关H-RAS的水平，一种专有法尼化的蛋白质，在轻度认知损害(MCI)和阿尔茨海默病(AD)患者与正常人的脑功能比较认知功能；法尼化H-RAS的水平与ERK的激活显著相关 H-RAS的主要下游效应因子。因此，我们假设蛋白质法尼化的上调是一种早期事件在阿尔茨海默病的致病级联和下游信号激活中起主要作用通路有助于认知障碍和神经病理的发展。这一中心假说将通过三个具体目标进行严格测试，使用创新的遗传、行为、电生理学和学前组方法。第一个目标是检验神经元特异性缺失的假设蛋白法尼化可减轻小鼠认知功能障碍、突触功能障碍和病理改变广告。目的2是检验H-RAS的缺失改善而H-RAS的过度激活的假设加重AD小鼠的认知/突触缺陷和病理。目标3是阐明两者之间的关系小鼠模型和人脑组织中AD病理和前烯基化蛋白的水平。总目标该项目的目的是揭开AD未被探索但潜在的关键致病机制，包括蛋白质预烯基化及其相关途径。澄清预烯基化和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。