How alpha-Synuclein misfolding promotes tau pathology in ADRD
How alpha-Synuclein misfolding promotes tau pathology in ADRD
批准号:
10285807
负责人:
Jonathan N Sachs
金额:
$37.73万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-01-01 至 2025-08-31
关键词:
Administrative SupplementAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAwardBehaviorBinding SitesBiologicalBiological AssayBiologyBiophysicsBiosensorCell modelCellsChemicalsClinical ResearchCollaborationsColorComplexCoupledDataDementia with Lewy BodiesDiseaseDown SyndromeEngineeringEnvironmentFluorescenceFluorescence Resonance Energy TransferFoundationsFrontotemporal DementiaGrantHomoHumanInvestigationKineticsLabelLeadLettersLewy BodiesLewy Body DiseaseMeasurementMethodsMicroscopyMinnesotaMolecularMonitorMorphologic artifactsNatureNeurodegenerative DisordersNeurologistNeuronsOutcomePaperParentsParkinson&aposs DementiaPathogenesisPathologicPathologyPhenotypePositioning AttributePresenile Alzheimer DementiaPrognosisProteinsProtocols documentationPublicationsRecording of previous eventsReproducibilityResearchResearch PersonnelResolutionScienceSeveritiesSignal TransductionStructureSubgroupSystemTauopathiesTechniquesTechnologyTestingTimeTotal Internal Reflection FluorescentToxic effectUniversitiesWorkalpha synucleinbasebiophysical toolscomorbiditydesigndrug discoveryinduced pluripotent stem cellinhibitor/antagonistinsightkinetic modelmouse modelmutantneuropathologynovel strategiesparent grantprotein misfoldingreal time monitoringresearch studyscreeningsmall moleculesmall molecule inhibitorsupport networksynucleinopathytau Proteinstau aggregationtau interactiontool
中文摘要
摘要
英文摘要
Abstract
The parent award to this Administrative Supplement for AD and ADRD research studies alpha-Synuclein
(aSyn) oligomerization in great biophysical detail, using state-of-the-art techniques (fluorescence lifetime FRET,
19F-NMR and TIRF microscopy). Here, we will use these same techniques to understand interactions between
aSyn and tau. These data will provide critically important insights into the pathological aSyn/tau interaction that
contributes to co-morbidities of various ADRD proteinopathies, including LBD and FTLD. This extension of the
original research—which will propel our groups from synucleinopathy to tauopathy research—is quite
straightforward, requiring no new materials or methods, but answering exciting new questions.
Neurodegenerative diseases are classified based on their predominant proteinopathy (e.g. tauopathies or
alpha-synucleinopathies). In tauopathies, misfolded tau (e.g. oligomers, PHF, and NFTs) commonly presents
with a comorbid proteinopathy that differs across AD and ADRDs with the severity of co-morbidity directly
associated with an adverse prognosis. Ignoring these comorbid proteinopathies likely impedes our
understanding of disease pathogenesis. In a recent clinical study comparison, alpha-synuclein (aSyn)
comorbidity in AD was described as an important biological subgroup of LBDs. This co-morbidity spans a broad
distribution of disorders, even being present in unimpaired aging. Specific to AD, aSyn-rich Lewy Bodies (LB)
were observed in the majority of sporadic AD cases (around 60%), familial AD cases (over 60%), and AD cases
with Down syndrome (over 50%). Conversely, AD neuropathology appears to contribute to the emergence of
dementia in PD and DLB; potentially acting synergistically with aSyn to spread aSyn associated pathology.
The hypothesis motivating this work is that the co-morbidity of tau and aSyn pathology in AD and related
dementias, including LBD and FLTD, is directly associated with tau’s propensity to interact with aSyn in early-
stage oligomeric complexes that form before insoluble fibrillar aggregates. In this supplement, we will test the
specific hypothesis that early-stage aSyn oligomers fundamentally alter tau structural biophysics in the cell, and
that these changes are an important determinant (and hence target) in pathology.
No biophysical data yet exists about how aSyn and tau co-mingle in early stages of misfolding in
cells, before fibrils form, nor how those interactions increase toxicity of the aggregates. The parent grant
uses our previously establish fluorescence lifetime FRET biosensors to focus on homo-oligomeric interactions
(e.g. aSyn-aSyn) in toxic, non-fibrillar oligomers that cause synucleinopathies. In this Supplement, we will use
our biosensors to define the biophysical basis for how hetero-oligomeric interactions form between aSyn and tau
in tauopathies, how these interactions lead to co-oligomerization, and how they impact tau pathology.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Elucidating the biophysics of pre-fibrillar, toxic tau oligomers: from amino acid motifs to neuronal dysfunction
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批准号:10461322
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项目类别:
-
资助金额:$52.44万
-
财政年份:2021
-
负责人:Jonathan N Sachs
-
依托单位:
Elucidating the biophysics of pre-fibrillar, toxic tau oligomers: from amino acid motifs to neuronal dysfunction
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批准号:10489810
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项目类别:
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资助金额:$52.94万
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财政年份:2021
-
负责人:Jonathan N Sachs
-
依托单位:
Exploiting New Fibril Structures to Understand the Biophysical Basis for Oligomerization and Toxicity of Alpha-Synuclein
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批准号:10684133
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项目类别:
-
资助金额:$37.99万
-
财政年份:2020
-
负责人:Jonathan N Sachs
-
依托单位:
Exploiting new fibril structures to understand the biophysical basis for oligomerization and toxicity of alpha-Synuclein
-
批准号:10468800
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项目类别:
-
资助金额:$38.62万
-
财政年份:2020
-
负责人:Jonathan N Sachs
-
依托单位:
Exploiting new fibril structures to understand the biophysical basis for oligomerization and toxicity of alpha-Synuclein
-
批准号:10042689
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项目类别:
-
资助金额:$41.21万
-
财政年份:2020
-
负责人:Jonathan N Sachs
-
依托单位:
Exploiting new fibril structures to understand the biophysical basis for oligomerization and toxicity of alpha-Synuclein
-
批准号:10267686
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项目类别:
-
资助金额:$39.14万
-
财政年份:2020
-
负责人:Jonathan N Sachs
-
依托单位:
Understanding the structural dynamics of TNF receptors
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批准号:10178044
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项目类别:
-
资助金额:$37.35万
-
财政年份:2019
-
负责人:Jonathan N Sachs
-
依托单位:
Understanding the structural dynamics of TNF receptors
-
批准号:10594464
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项目类别:
-
资助金额:$37.35万
-
财政年份:2019
-
负责人:Jonathan N Sachs
-
依托单位:
Understanding the structural dynamics of TNF receptors
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批准号:10379462
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项目类别:
-
资助金额:$37.35万
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财政年份:2019
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负责人:Jonathan N Sachs
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依托单位:
Understanding and targeting the Methionine-Aromatic motif in oxidized alpha-Synuclein
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批准号:9791033
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项目类别:
-
资助金额:$17.64万
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财政年份:2018
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负责人:Jonathan N Sachs
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依托单位:
Understanding and targeting the Methionine-Aromatic motif in oxidized alpha-Synuclein
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批准号:9649001
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项目类别:
-
资助金额:$21.49万
-
财政年份:2018
-
负责人:Jonathan N Sachs
-
依托单位:
Dynamics of transmembrane dimers in TNF-Receptors by EPR and molecular simulation
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批准号:8827818
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项目类别:
-
资助金额:$33.18万
-
财政年份:2014
-
负责人:Jonathan N Sachs
-
依托单位:
Dynamics of transmembrane dimers in TNF-Receptors by EPR and molecular simulation
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批准号:9250185
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项目类别:
-
资助金额:$33.18万
-
财政年份:2014
-
负责人:Jonathan N Sachs
-
依托单位:
Dynamics of transmembrane dimers in TNF-Receptors by EPR and molecular simulation
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批准号:8693092
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项目类别:
-
资助金额:$34.48万
-
财政年份:2014
-
负责人:Jonathan N Sachs
-
依托单位:
Modeling synaptic vesicles: how does alpha-Synuclein inhibit fusion?
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批准号:8611379
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项目类别:
-
资助金额:$34.87万
-
财政年份:2013
-
负责人:Jonathan N Sachs
-
依托单位:
Modeling synaptic vesicles: how does alpha-Synuclein inhibit fusion?
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批准号:9132373
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项目类别:
-
资助金额:$35.46万
-
财政年份:2013
-
负责人:Jonathan N Sachs
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依托单位:
THE EFFECT OF ?-SYNUCLEIN ON MEMBRANE STRUCTURE
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批准号:8364360
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项目类别:
-
资助金额:$0.11万
-
财政年份:2011
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负责人:Jonathan N Sachs
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依托单位:
Sulfur-pi: a highly stabilizing binding motif in TNF receptors
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批准号:8082711
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项目类别:
-
资助金额:$17.71万
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财政年份:2010
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负责人:Jonathan N Sachs
-
依托单位:
Sulfur-pi: a highly stabilizing binding motif in TNF receptors
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批准号:7962481
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项目类别:
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资助金额:$15.19万
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财政年份:2010
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负责人:Jonathan N Sachs
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依托单位:
What controls the thickness of biological membranes
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批准号:6790196
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项目类别:
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资助金额:$4.11万
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财政年份:2004
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负责人:Jonathan N Sachs
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依托单位:
海外基金