Connecting long-lived protein isomerization to lysosomal failure in Alzheimer's disease

将长寿命蛋白质异构化与阿尔茨海默氏病溶酶体衰竭联系起来

基本信息

批准号：
10377485
负责人：
Ryan Roy Julian
金额：
$ 53.52万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10377485
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Amino Acids Amyloid beta-Protein Behavior Biochemical Brain Cells Chemicals Chemistry Crystalline Lens Data Dementia Destinations Digestion Disease Dissociation Enzymes Event Exhibits Failure Genetic Goals Human Hydrolase Investigation Lead Location Lysosomes Mass Spectrum Analysis Measures Methods Modeling Modification Mutate Mutation Neurofibrillary Tangles Pathogenicity Pathology Pathway interactions Peptide Fragments Peptide Hydrolases Peptides Persons Positioning Attribute Post-Translational Protein Processing Prevalence Protein Fragment Proteins Proteolysis Resources Senile Plaques Site Structure System Techniques Technology Testing Tissue Sample Variant age related amyloid formation base brain tissue epimerization experimental study liquid chromatography mass spectrometry lysosomal proteins mind control novel therapeutic intervention prevent tau Proteins

项目摘要

Summary Alzheimer’s disease (AD) is the most common cause of dementia and affects approximately 50 million people worldwide. Although significant resources have been invested, successful therapies have yet to be discovered, suggesting that alternative approaches may be needed. This proposal will investigate a new idea connecting modifications spontaneously occurring in long-lived proteins to the underlying causes of AD. These modifications, known as isomerization and epimerization, represent structural changes that significantly perturb the behavior of affected proteins. These modifications have largely escaped prior investigation because they have historically been difficult to detect, but recent advances in technology have enabled their identification and characterization on a larger scale than previously possible. We will use these methods to fully characterize these modifications in a protein called tau and the amyloid beta peptide, which are both intricately involved in the progression of AD. We will also explore the underlying chemistry leading to the formation of isomerization and epimerization and the rates at which they accrue. Importantly, we hypothesize that these modifications prevent long-lived proteins from being broken down and recycled in the lysosome. This hypothesis is supported by preliminary results and, importantly, provides a pathway that could eventually explain the lysosomal malfunction that is known to occur in AD and is among the earliest observable problems at the cellular level. We will perform experiments to determine whether any of the lysosomal proteases, the molecules responsible for degrading proteins, are able to digest the modified proteins. Undigested protein fragments persisting in the lysosome due to isomerization or epimerization would be subject to accumulation. This failure closely parallels events occurring with undigested substrates in lysosomal storage disorders and provides a potential explanation for the previously observed connections between the two diseases, which exhibit similar pathology. The ultimate goal of this project is to establish that modifications to long-lived proteins initiate events that ultimately lead to lysosomal failure in AD, which will open up new therapeutic strategies for exploration.

概括阿尔茨海默氏病（AD）是痴呆症的最常见原因，影响约5000万全球人。尽管已经投资了大量资源，但成功的疗法尚未被发现，表明可能需要替代方法。该建议将调查新想法连接了在长寿命蛋白中发生的类似于赞助商的赞助商与底层广告原因。这些修饰称为异构化和发作，代表结构性显着扰动受影响蛋白的行为的变化。这些修改在很大程度上由于历史上很难检测到事先调查，因此逃脱了，但是最近的进步在技术中，比以前更大的规模使他们的身份和表征能够可能的。我们将使用这些方法在称为tau的蛋白质中充分表征这些修饰和淀粉样蛋白β胡椒，它们都与AD的进展相关。我们也会探索导致异构化和情节形成的基本化学反应以及他们积累的费率。重要的是，我们假设这些修饰可以阻止长寿蛋白质被分解并回收在溶酶体中。该假设得到初步结果，重要的是提供了一种最终可以解释溶酶体的途径已知发生在AD中的故障，是细胞最早可观察的问题之一等级。我们将执行实验以确定是否有任何溶酶体蛋白酶，分子负责降解蛋白质，能够消化修饰的蛋白质。未消除的蛋白质由于异构化或发作会持续存在于溶酶体中的片段或发作将受到积累。这种故障与溶酶体中的无问题的底物的事件紧密相似存储障碍，并为先前观察到的连接提供了潜在的解释在两种疾病之间表现出相似的病理。该项目的最终目标是确定对长寿命蛋白的修改会引发最终导致溶酶体衰竭的事件在广告中，这将开辟新的探索治疗策略。