Uncovering the roles of ubiquitination and the ESCRT pathway in degradative sorting of SV proteins.
揭示泛素化和 ESCRT 通路在 SV 蛋白降解分选中的作用。
基本信息
- 批准号:10364729
- 负责人:
- 金额:$ 38.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-01-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAlzheimer&aposs disease modelAmericanAnimal ModelAxonAxonal TransportBiochemicalBiological AssayBiotinylationCaringCarrier ProteinsCharacteristicsCommunicationComplexDOOR (deafness-onychodystrophy-osteodystrophy-retardation) syndromeDataDeubiquitinating EnzymeDiseaseElectron MicroscopyEpilepsyEtiologyEventExhibitsFluorescenceGenesGoalsHealth systemHippocampus (Brain)ImageImpairmentIntellectual functioning disabilityKinesinLeadLipidsLysosomesMediatingMembraneMembrane ProteinsMolecularMonitorMonomeric GTP-Binding ProteinsMorphologyMovementMultivesicular BodyMutationNerve DegenerationNervous system structureNeurodegenerative DisordersNeurogliaNeuronsNeurotransmittersOrganellesParkinson DiseaseParkinsonian DisordersPathway interactionsPhenotypePresynaptic TerminalsProcessProductionProductivityProtein SortingsProteinsRecyclingResolutionRoleSeriesSiteSorting - Cell MovementSynapsesSynaptic CleftSynaptic VesiclesTechniquesTestingUCHL1 geneUbiquitinUbiquitinationVesicleWorkcell motilitycostexperimental studyfirst responderfluorescence imaginghepatocyte growth factor-regulated tyrosine kinase substrateimaging approachinsightloss of functionnervous system disorderneural circuitneural networkneurotransmissionneurotransmitter releasephosphatidylinositol 3-phosphatepresynapticpreventprotein complexprotein degradationprotein transportproteostasisrecruitresponsetraffickingubiquitin isopeptidasevesicle transportvesicular SNARE proteins
项目摘要
PROJECT SUMMARY
Synaptic vesicles (SVs) are highly specialized organelles that store and release neurotransmitters. The
accumulation of old or damaged proteins on SVs compromises neurotransmission and can lead to
dysfunctional neural circuits and networks. Indeed, recent studies have shown that mutations in genes that
regulate SV protein degradation are associated with neurological and neurodegenerative disorders,
demonstrating the critical importance of SV protein turnover for nervous system health. Yet the molecular
mechanisms responsible for SV turnover and degradation remain poorly understood. The overall goal of this
project is to elucidate these mechanisms, providing critical insights into the etiology of diseases that afflict
millions of Americans. Our recent work has shown that the ESCRT pathway mediates the activity-dependent
degradation of SV membrane proteins. The ESCRT pathway comprises a series of protein complexes that
sequentially recruit ubiquitinated cargo and catalyze the formation of multivesicular bodies (MVBs) for delivery
of these cargo to lysosomes. Intriguingly, we find that increased neuronal firing stimulates the activation of
de/ubiquitinating enzymes at the synapse, as well as the motility of axonal transport vesicles carrying initial
ESCRT protein Hrs, and their recruitment to SV pools. We hypothesize that these events are critical rate-
limiting steps for activity-dependent turnover of SV membrane proteins. We will test this hypothesis with three
aims. In Aim 1, we will evaluate the role of de/ubiquitination in the recycling of SV membrane proteins. Here,
we will use biochemical and fluorescence imaging assays to evaluate how ubiquitination regulates SV protein
recycling vs. degradation in hippocampal neurons. We will also investigate whether the deubiquitinating
enzyme UCHL1 is necessary for maintaining SV proteins on recycling SVs, counteracting their degradative
sorting. In Aim 2, we will characterize Hrs vesicles and the impact of Hrs on downstream ESCRT protein
recruitment to SV pools. We will use super-resolution fluorescence/electron microscopy and proximity
biotinylation to characterize the morphology and molecular composition of these vesicles, and Hrs gain- and
loss-of-function combined with live imaging to determine whether the recruitment of downstream ESCRT
proteins to SV pools requires Hrs. In Aim 3, we will investigate the mechanisms of activity-dependent Hrs
recruitment to SV pools. We will test the roles of specific kinesins in the axonal transport of Hrs, and test
whether its recruitment to SV pools requires the lipid PI(3)P, the presence of ubiquitinated proteins, and/or the
small GTPase Rab35. Together, these studies will uncover fundamental mechanisms underlying SV
proteostasis in neurons.
项目总结
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)
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Clarissa Leigh Waites其他文献
Clarissa Leigh Waites的其他文献
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{{ truncateString('Clarissa Leigh Waites', 18)}}的其他基金
Uncovering stress-induced mechanisms of Tau pathology in Alzheimer's disease
揭示阿尔茨海默病中压力诱导的 Tau 病理机制
- 批准号:
10098370 - 财政年份:2020
- 资助金额:
$ 38.26万 - 项目类别:
Uncovering the roles of ubiquitination and the ESCRT pathway in degradative sorting of SV proteins.
揭示泛素化和 ESCRT 通路在 SV 蛋白降解分选中的作用。
- 批准号:
10162269 - 财政年份:2020
- 资助金额:
$ 38.26万 - 项目类别:
High-throughput screening platform for discovery of fluorescent synaptic markers
用于发现荧光突触标记的高通量筛选平台
- 批准号:
8769206 - 财政年份:2014
- 资助金额:
$ 38.26万 - 项目类别:
Uncovering the Roles of Ubiquitination and the ESCRT Pathway in Degradative Sorting of SV Proteins.
揭示泛素化和 ESCRT 途径在 SV 蛋白降解分选中的作用。
- 批准号:
10576875 - 财政年份:2014
- 资助金额:
$ 38.26万 - 项目类别:
High-throughput screening platform for discovery of fluorescent synaptic markers
用于发现荧光突触标记的高通量筛选平台
- 批准号:
8910791 - 财政年份:2014
- 资助金额:
$ 38.26万 - 项目类别:
Elucidating a molecular pathway for synaptic vesicle maintenance and degradation
阐明突触小泡维持和降解的分子途径
- 批准号:
8765805 - 财政年份:2014
- 资助金额:
$ 38.26万 - 项目类别:
Elucidating a molecular pathway for synaptic vesicle maintenance and degradation
阐明突触小泡维持和降解的分子途径
- 批准号:
8578781 - 财政年份:2013
- 资助金额:
$ 38.26万 - 项目类别:
Elucidating a molecular pathway for synaptic vesicle maintenance and degradation
阐明突触小泡维持和降解的分子途径
- 批准号:
8672702 - 财政年份:2013
- 资助金额:
$ 38.26万 - 项目类别:
Elucidating a molecular pathway for synaptic vesicle maintenance and degradation
阐明突触小泡维持和降解的分子途径
- 批准号:
8899649 - 财政年份:2013
- 资助金额:
$ 38.26万 - 项目类别:
The role of dense core vesicles in synapse formation
致密核心囊泡在突触形成中的作用
- 批准号:
6893692 - 财政年份:2003
- 资助金额:
$ 38.26万 - 项目类别: