The Function of Synuclein
突触核蛋白的功能
基本信息
- 批准号:10569089
- 负责人:
- 金额:$ 50.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsBehaviorBindingBiological AssayCatecholaminesCell membraneChromaffin CellsChromaffin granuleCytoplasmic GranulesCytoskeletonDataDense Core VesicleDiseaseDyesEarly InterventionElectron MicroscopyEventExocytosisHuman GeneticsIdiopathic Parkinson DiseaseImageImpairmentIn VitroIndividualInheritedKnockout MiceMembraneMembrane FusionMethodsMonitorMutationN-terminalNerve DegenerationNervous SystemNeuromodulatorNeuronsNeurotransmittersParkinson DiseasePathogenesisPathogenicityPatientsPeptidesPhosphorylationPhosphorylation SiteProcessProteinsRegulationResolutionRoleRunningSecretory VesiclesSignal TransductionStructureSynaptic VesiclesSystemTerminal Repeat SequencesTestingTimeVesicleWorkalpha synucleingenetic manipulationlight microscopymillisecondpharmacologicpostsynapticpresynapticprogramsresponsesealsynucleintoolvesicular release
项目摘要
Signaling in the nervous system depends on the regulated exocytosis of specialized secretory vesicles.
Membrane fusion initiates the process of release, but behavior of the pore formed by fusion can control the rate,
extent and identity of what is released. Indeed, the fusion pore can reseal before full vesicle collapse into the
plasma membrane, potentially trapping unreleased cargo in a form of exocytosis known as `kiss-and-run', a
regulatory mechanism well-established for large dense core vesicles (LDCVs), which release neuromodulators.
However, the mechanisms that regulate behavior of the fusion pore have remained unclear and its role in the
release of classical neurotransmitters from synaptic vesicles (SVs) has been controversial. The actin
cytoskeleton and its associated proteins have been suggested to influence pore behavior but the role has
remained unclear.
The presynaptic protein α-synuclein has a central role in the pathogenesis of Parkinson's disease (PD).
Human genetics shows that mutations in synuclein can cause the disease and the protein accumulates in all
patients with the idiopathic disorder. Like other proteins important for neurodegeneration, however, its normal
function has remained unknown. Using knockout mice and imaging by light and electron microscopy, we have
found that endogenous synuclein normally regulates the fusion pore formed by both LDCVs and SVs, thus
influencing the mode of release. The long-term objectives of this program are to understand how synuclein
cooperates with other cellular factors to promote fusion pore dilation and how a disturbance in this activity
contributes to disease. Since the available methods have limited analysis of the fusion pore and vesicle collapse,
we have developed new methods to image the full scope of exocytosis by individual vesicles. Using these, we
will study the role of synuclein in pore dilation and membrane collapse by both large dense core vesicles and
synaptic vesicles. Specifically, we propose to
1) Characterize the role of synuclein in exocytosis by imaging at high resolution with several complementary
methods, including false fluorescent neurotransmitters and Alexa dye entry.
2) Assess the interaction of synuclein with the actin cytoskeleton. Observations in multiple systems have
implicated the actin cystoskeleton in exocytosis including pore dilation and we will determine whether synuclein
acts through a common or independent mechanism.
3) Determine how the structure of α-synuclein contributes to its role in exocytosis. We will determine how the N-
terminal repeats and C-terminus contribute to normal function. We will test the role of established
phosphorylation sites since they may contribute to idiopathic disease by mimicking inherited mutations.
神经系统中的信号依赖于特殊分泌囊泡的胞外分泌调节。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
High-speed imaging reveals the bimodal nature of dense core vesicle exocytosis.
- DOI:10.1073/pnas.2214897120
- 发表时间:2023-01-03
- 期刊:
- 影响因子:11.1
- 作者:Zhang P;Rumschitzki D;Edwards RH
- 通讯作者:Edwards RH
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ROBERT H EDWARDS其他文献
ROBERT H EDWARDS的其他文献
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{{ truncateString('ROBERT H EDWARDS', 18)}}的其他基金
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
- 批准号:
9258506 - 财政年份:2015
- 资助金额:
$ 50.35万 - 项目类别:
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
- 批准号:
9920217 - 财政年份:2015
- 资助金额:
$ 50.35万 - 项目类别:
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
- 批准号:
8964141 - 财政年份:2015
- 资助金额:
$ 50.35万 - 项目类别:
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
- 批准号:
10614384 - 财政年份:2015
- 资助金额:
$ 50.35万 - 项目类别:
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
- 批准号:
10392888 - 财政年份:2015
- 资助金额:
$ 50.35万 - 项目类别:
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