Quality control of APP cleavage by RING-finger ubiquitin ligases

通过环指泛素连接酶进行 APP 切割的质量控制

• 批准号: 9308437
• 负责人: Mervyn J Monteiro
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308437
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Binding; Biological Assay; Brain; Caring; Cells; Cleaved cell; Clinical; Cognition; Complex; Data; Defect; Degradation Pathway; Dementia; Deposition; Disease; Dominant-Negative Mutation; Ensure; Enzymes; Foundations; Generations; Human; Human Genome; Immunoblotting; Immunoprecipitation; Incidence; Investigation; Lead; Lesion; Ligase; Link; Membrane; Membrane Proteins; Memory; Molecular; Morphologic artifacts; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Physiologic pulse; Play; Process; Property; Proteins; Proteolysis; Quality Control; Research; Research Personnel; Rest; Ring Finger Domain; Role; Senile Plaques; Site; System; Tissue Model; amyloid precursor protein processing; cost; effective therapy; experimental study; extracellular; human tissue; insight; knock-down; mouse model; mutant; nervous system disorder; neuron loss; new therapeutic target; novel; novel therapeutics; overexpression; prevent; protein complex; protein metabolism; protein transport; proteostasis; screening; tau Proteins; ubiquitin ligase

Summary Alzheimer's disease (AD) is the most common cause of dementia that affects approximately 5.3 million people in the USA today. The incidence of AD increases dramatically with age, affecting ~7% of people by the age of 65 years and 45% by the age of 85 years. The cost of caring and treating AD patients today is ~$172 billion, but it is predicted to rise dramatically by the year 2050 because of an anticipated four-fold increase in AD. AD is clinically distinguished by severe loss of both memory and cognition, and pathologically by massive neuron loss combined with increased deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT) in the brain. Amyloid plaques are composed principally of small proteolytic fragments of the amyloid precursor protein (APP), whereas NFT are composed of abnormally modified forms of tau protein. There is considerable debate as to the exact cause(s) of AD, however it is generally agreed that the two lesions, the plaques and tangles, are somehow inextricably linked to the disease. An understanding of how APP is processed to generate the potentially toxic amyloid β fragments (Aβ) that accumulate in plaques has become a central focus of much AD research. These studies have revealed that processing of APP is complex, but, for simplicity sake, it has been divided into the non- amyloidogenic and amyloidogenic pathways. Currently, there is no effective treatment that delays or prevents AD. Part of this problem might be that researchers have focused on solutions that might be too downstream of the instigating molecular insults. The foundation of this proposal rests on the increasing evidence that disturbances in protein homeostasis, arising from defects in protein quality control systems, play in many neurodegenerative disorders. Our hypothesis is that malfunction of ubiquitin ligases that function as key regulators of protein quality control systems cause abnormalities in APP processing that is directly linked to AD pathogenesis. Accordingly, we propose that the identification of ubiquitin ligases that alter APP processing might provide new therapeutic targets for preventing and treating AD. However, the human genome contains several hundred ubiquitin ligases and the challenge is to find which ones regulate APP processing and potentially AD pathogenesis. We propose a practicable strategy to screen and identify ligases that regulate APP processing. Indeed we provide preliminary data that suggests it is not only possible to find these ligases, but that some ubiquitin ligases might be beneficial by shifting APP processing to a predominantly non-amyloidogenic pathway, whereas others might be detrimental and shift APP processing in the opposite way, to the amyloidogenic pathway. We articulate the rationale and research strategy for why, and how investigation into these ligases could provide novel therapeutic opportunities to treat AD.

摘要 阿尔茨海默病(AD)是痴呆症最常见的原因，影响了大约530万人 今天的美国人。阿尔茨海默病的发病率随着年龄的增长而急剧增加，影响到约7%的人 65岁，到85岁时达到45%。如今，护理和治疗AD患者的成本是 ~1720亿美元，但预计到2050年将大幅增长，因为预计将增长四倍 AD增加。AD的临床特点是严重的记忆和认知丧失，以及 病理上由大量神经元丢失和细胞外淀粉样斑块沉积增加所致 以及大脑中的细胞内神经原纤维缠结(NFT)。淀粉样斑块主要由 淀粉样前体蛋白(APP)的小蛋白分解片段，而NFT由 Tau蛋白的异常修饰形式。关于AD的确切原因(S)，有相当大的争论， 然而，人们普遍认为，斑块和缠结这两种病变在某种程度上是无法解决的。 与这种疾病有关。了解APP如何处理以产生潜在有毒的淀粉样蛋白β 聚集在斑块中的碎片(Aβ)已成为许多AD研究的中心焦点。这些研究 已经透露了APP的处理是复杂的，但为了简单起见，它被分为非 淀粉样变性和淀粉样变性途径。目前，还没有有效的治疗方法来延迟或 预防AD。这个问题的部分原因可能是研究人员关注的解决方案可能太过 在挑起分子侮辱的下游。这项建议的基础是不断增加的 有证据表明，由蛋白质质量控制系统缺陷引起的蛋白质动态平衡紊乱， 在许多神经退行性疾病中发挥作用。我们的假设是泛素的功能障碍会导致 作为蛋白质质量控制系统的关键调节器的功能会导致APP处理异常，即 与AD的发病机制直接相关。因此，我们认为，泛素连接酶的鉴定 ALTER APP加工可能为AD的防治提供新的治疗靶点。然而， 人类基因组包含数百个泛素连接酶，挑战是找到哪些泛素连接酶调节 APP处理和潜在的AD发病机制。我们提出了一个可行的策略来筛选和识别 调节应用程序处理的连接酶。事实上，我们提供的初步数据表明，不仅是 有可能找到这些连接酶，但一些泛素连接酶可能会通过转移应用程序处理而受益 转到以非淀粉样变为主的途径，而其他途径可能是有害的，并转移APP 以相反的方式处理，到淀粉样蛋白生成途径。我们清楚地阐述了理论基础和研究 为什么，以及如何研究这些连接酶可以提供新的治疗机会 治疗AD。