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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.

摘要阿尔茨海默病(AD)是导致痴呆症的最常见原因，影响着大约5000万人世界各地的人们。尽管已经投入了大量的资源，但成功的治疗方法还没有被发现，这表明可能需要其他方法。该提案将调查一项将长寿命蛋白质中自发发生的修饰与潜在的阿尔茨海默病的病因。这些修饰，称为异构化和异构化，代表结构显著扰乱受影响蛋白质行为的变化。这些修改在很大程度上逃脱了先前的调查，因为它们在历史上很难被发现，但最近的进展在技术上已经能够在比以前更大的范围内识别和表征它们有可能。我们将使用这些方法在一种名为tau和tau的蛋白质中完全表征这些修饰淀粉样β蛋白，两者都错综复杂地参与了AD的进展。我们还将探索导致异构化和异构化形成的潜在化学和它们累积的利率。重要的是，我们假设这些修改阻止了长寿命防止蛋白质在溶酶体中被分解和循环。这一假设得到了初步结果，重要的是，提供了一条最终可能解释溶酶体的途径已知在AD中发生的故障，是细胞中最早可观察到的问题之一水平。我们将进行实验，以确定是否有任何溶酶体蛋白水解酶，分子负责降解蛋白质，能够消化修饰后的蛋白质。未消化的蛋白质由于异构化或异构化而持续存在于溶酶体中的片段会受到积累。这一失败与溶酶体中未消化底物发生的事件密切相关。并为之前观察到的连接提供了一个可能的解释这两种疾病表现出相似的病理特征。这个项目的最终目标是确定对长寿命蛋白质的修饰启动了最终导致溶酶体失败的事件这将为探索开辟新的治疗策略。