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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：
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
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/10600990
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 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

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.

总结