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:
- 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
- 来源:
- 关键词:AffectAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAmino AcidsAmyloid beta-ProteinBehaviorBiochemicalBrainCellsChemicalsChemistryCrystalline LensDataDementiaDestinationsDigestionDiseaseDissociationEnzymesEventExhibitsFailureGeneticGoalsHumanHydrolaseInvestigationLeadLocationLysosomesMass Spectrum AnalysisMeasuresMethodsModelingModificationMutateMutationNeurofibrillary TanglesPathogenicityPathologyPathway interactionsPeptide FragmentsPeptide HydrolasesPeptidesPersonsPositioning AttributePost-Translational Protein ProcessingPrevalenceProtein FragmentProteinsProteolysisResourcesSenile PlaquesSiteStructureSystemTechniquesTechnologyTestingTissue SampleVariantage relatedamyloid formationbasebrain tissueepimerizationexperimental studyliquid chromatography mass spectrometrylysosomal proteinsmind controlnovel therapeutic interventionpreventtau 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Ryan Roy Julian其他文献
Ryan Roy Julian的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
10600990 - 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: