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:
  • 金额:
    $ 53.52万
  • 依托单位:
  • 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

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

项目成果

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Ryan Roy Julian其他文献

Ryan Roy Julian的其他文献

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{{ truncateString('Ryan Roy Julian', 18)}}的其他基金

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:
    10377485
  • 财政年份:
    2020
  • 资助金额:
    $ 53.52万
  • 项目类别:
Identification of peptide epimers in crystallin proteins
晶状体蛋白中肽差向异构体的鉴定
  • 批准号:
    8901229
  • 财政年份:
    2014
  • 资助金额:
    $ 53.52万
  • 项目类别:
Identification of peptide epimers in crystallin proteins
晶状体蛋白中肽差向异构体的鉴定
  • 批准号:
    9306129
  • 财政年份:
    2014
  • 资助金额:
    $ 53.52万
  • 项目类别:
Rapid ultra-sensitive three dimensional protein structure determination by mass s
通过质量数快速测定超灵敏三维蛋白质结构
  • 批准号:
    8319335
  • 财政年份:
    2011
  • 资助金额:
    $ 53.52万
  • 项目类别:
Rapid ultra-sensitive three dimensional protein structure determination by mass s
通过质量数快速测定超灵敏三维蛋白质结构
  • 批准号:
    8164717
  • 财政年份:
    2011
  • 资助金额:
    $ 53.52万
  • 项目类别:
Rapid ultra-sensitive three dimensional protein structure determination by mass s
通过质量数快速测定超灵敏三维蛋白质结构
  • 批准号:
    8510672
  • 财政年份:
    2011
  • 资助金额:
    $ 53.52万
  • 项目类别:
Probing Natively Disordered Proteins with Selective Noncovalent Adduct Protein Pr
用选择性非共价加合物蛋白 Pr 探测天然无序蛋白
  • 批准号:
    7945317
  • 财政年份:
    2009
  • 资助金额:
    $ 53.52万
  • 项目类别:
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