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
- 来源:
- 关键词:AffectAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAmino AcidsAmyloid beta-ProteinBehaviorBiochemicalBrainCellsChemicalsChemistryCrystalline LensDataDementiaDestinationsDigestionDiseaseDissociationEnzymesEventExhibitsFailureGeneticGoalsHumanHydrolaseInvestigationInvestmentsIsomerismLocationLysosomesMapsMass Spectrum AnalysisMeasuresMethodsModelingModificationMutateMutationNeurofibrillary TanglesPathogenicityPathologyPathway interactionsPeptide FragmentsPeptide HydrolasesPeptidesPersonsPositioning AttributePost-Translational Protein ProcessingPrevalenceProtein FragmentProteinsProteolysisResourcesSenile PlaquesSiteStructureSystemTechniquesTechnologyTestingTissue SampleVariantage relatedamyloid formationbrain tissueepimerizationexperimental studyliquid chromatography mass spectrometrylysosomal proteinsmind controlnovel therapeutic interventionpostmitoticpreventtau 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
项目成果
期刊论文数量(0)
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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: