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

• 批准号: 10600990
• 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
• 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/10600990
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' 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; Investments; Isomerism; Location; Lysosomes; Maps; 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; brain tissue; epimerization; experimental study; liquid chromatography mass spectrometry; lysosomal proteins; mind control; novel therapeutic intervention; postmitotic; prevent; tau Proteins

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.

总结 阿尔茨海默病（AD）是痴呆症的最常见原因，影响约5000万人 世界各地的人们。尽管已经投入了大量资源，但成功的治疗方法还没有出现。 这表明可能需要其他方法。该提案将调查 一个新的想法，将长寿命蛋白质中自发发生的修饰与潜在的 AD的原因这些修饰，称为异构化和差向异构化，代表了结构上的改变。 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 因为它们在历史上很难被发现，所以逃过了先前的调查，但最近的进展 技术上的进步使它们能够在比以前更大的规模上被识别和表征 可能我们将使用这些方法来充分表征一种名为tau的蛋白质中的这些修饰， 淀粉样β肽，两者都复杂地参与了AD的进展。我们还将 探索导致异构化和差向异构化形成的潜在化学过程， 它们的累积率。重要的是，我们假设这些修饰阻止了长寿命的 蛋白质在溶酶体中被分解和回收。这一假设得到了 初步结果，重要的是，提供了一个途径，最终可以解释溶酶体 已知发生在AD中的故障，并且是在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酶，分子 负责降解蛋白质，能够消化修饰的蛋白质。未消化蛋白质 由于异构化或差向异构化而在溶酶体中持续存在的片段将受到 积累这种失败与溶酶体中未消化底物发生的事件密切相关。 存储障碍，并为先前观察到的连接提供了一个潜在的解释 这两种疾病之间的差异，表现出相似的病理。该项目的最终目标是 确定对长寿命蛋白质的修饰会引发最终导致溶酶体衰竭的事件 这将为探索新的治疗策略开辟道路。