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.

项目摘要致病机制是阿尔茨海默氏病（AD）的发展仍然难以捉摸。有趣的是，新兴的证据表明，蛋白质的翻译后脂质修饰，称为前化，可能在AD的发病机理中起重要作用。将异on-的前胞质膜（无论是法尼基或黄烷基焦磷酸）与具有A的蛋白质特征C末端基序。介导蛋白质相互作用。与异源三聚体G蛋白的超家族有关调节AD中的各种细胞过程。蛋白质前化的作用不流动。影响淀粉样蛋白-β（Aβ）和TAU水平，神经炎症，突触塑料和认知功能。霍弗（Howver），大多数研究是在体外和药理学中进行的。我们最近的遗传方法的生产而不是直接调节蛋白质。研究表明，这两种蛋白质原始途径起着不同的神经生理作用丙烯酸化挽救认知功能并减少Aβ病理学降低蛋白质香烷基化导致对突触功能的不利影响。膜相关的H-RAS的水平，一种排除蛋白，在与正常患者相比，轻度认知障碍（MCI）和AD患者的大脑认知功能和丙烯酸H-RAS的水平与ERK的激活显着相关 H-Ras的主要下游效应子。早期事件在AD的病原级联和下游信号的激活中起主要重要性途径有助于认知障碍和神经病理学的发展将通过创新的遗传，行为，行为的组合对三个特定目标进行严格测试电生理学和前方法1是为了测试神经元特异性缺失蛋白质法尼化可以减轻鼠标中的认知缺陷，突触功能障碍和病理学 AD AIM 2是测试删除H-RAS的假设，而H-RAS的过度激活加剧AD小鼠的认知/突触缺陷和病理。 AD病理和小鼠模型和人脑组织中的蛋白质水平该项目的是揭开AD涉及的AD的未经置换的对接批判性致病机制蛋白质前化和相关途径。变革性发现并导致新的治疗策略的发展。