Wrd-specific PP2A substrates that regulate AZ stability

调节 AZ 稳定性的 Wrd 特异性 PP2A 底物

基本信息

  • 批准号:
    9137739
  • 负责人:
  • 金额:
    $ 18.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-09-15 至 2018-09-14
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Wrd-specific PP2A substrates that regulate AZ stability Project Summary / Abstract Neuronal communication depends on the precisely orchestrated release of neurotransmitters at specialized membrane compartments at the axonal terminal called active zones (AZs). Understanding how AZs are assembled and stabilized during development and activity-driven structural plasticity is key to understanding how neural circuitries are established and modified in healthy brains, and how dysfunction in synaptic formation contributes to pathogenesis of neurodevelopment disorders such as autism. A group of evolutionarily conserved presynaptic scaffolding proteins at the cytomatrix of AZ are thought to organize AZ assembly, however, the precise molecular mechanisms remain enigmatic. We recently showed that two master AZ organizers, Syd-1 and Liprin-α, regulate a specific PP2A activity through a AZ-localized PP2A B' regulatory subunit Well-rounded (Wrd) in a linear pathway to stabilize AZ materials and synaptic vesicles at the nerve terminal, and that this pathway antagonizes GSK-3β activity to prevent ectopic accumulation of synaptic materials at the distal axon region. Based on these findings, we hypothesize that Syd-1 and Liprin-α control PP2A/Wrd-mediated dephosphorylation events at the nerve terminal, which antagonize GSK-3β-mediated phosphorylation events to stabilize AZs at nerve terminal. Our preliminary data suggest that Futsch, a microtubule associated protein, is a potential substrate of both Wrd and GSK-3β. We will test the hypothesis that the syd-1/liprin-α/wrd phosphatase pathway and GSK-3β kinase pathway target Futsch to balance AZ retention at the nerve terminal (Aim1). We will also perform unbiased proteomic screens for downstream substrates of Syd-1-Liprin-α-PP2A/Wrd and GSK-3β, and test whether their phosphorylation and dephosphorylation can dynamically regulate AZ stability (Aim2).
 描述(由申请人提供):调节AZ稳定性的神经元特异性PP 2A底物项目概述/摘要神经元通信依赖于在轴突末端的专门膜隔室(称为活性区(AZ))处神经递质的精确编排的释放。了解AZ在发育过程中如何组装和稳定以及活动驱动的结构可塑性是了解神经回路如何在健康大脑中建立和修改以及突触形成功能障碍如何导致神经发育障碍(如自闭症)发病的关键。在AZ的细胞基质中,一组进化上保守的突触前支架蛋白被认为是组织AZ组装的,然而,精确的分子机制仍然是谜。我们最近发现,两个主要的AZ组织者,Syd-1和Liprin-α,通过一个位于AZ的PP 2A B'调节亚基Well-rounded(Well-rounded,Well-rounded)在一条线性通路中调节一个特定的PP 2A活性,以稳定神经末梢的AZ物质和突触囊泡,并且该通路拮抗GSK-3β活性,以防止突触物质在远端轴突区域的异位积聚。基于这些发现,我们推测Syd-1和Liprin-α控制PP 2A/P2 D介导的神经末梢去磷酸化事件,其拮抗GSK-3β介导的磷酸化事件以稳定神经末梢的AZs。我们的初步数据表明,Futsch,一种微管相关蛋白,是一种潜在的底物,这两种药物的活性。我们将检验syd-1/liprin-α/wrd磷酸酶通路和GSK-3β激酶通路靶向Futsch以平衡AZ在神经末梢(Aim 1)的保留的假设。我们还将对Syd-1-Liprin-α-PP 2A/Liprin d和GSK-3β的下游底物进行无偏蛋白质组学筛选,并测试其磷酸化和去磷酸化是否可以动态调节AZ稳定性(Aim 2)。

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)
Arl2- and Msps-dependent microtubule growth governs asymmetric division.
  • DOI:
    10.1083/jcb.201503047
  • 发表时间:
    2016-03-14
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Chen K;Koe CT;Xing ZB;Tian X;Rossi F;Wang C;Tang Q;Zong W;Hong WJ;Taneja R;Yu F;Gonzalez C;Wu C;Endow S;Wang H
  • 通讯作者:
    Wang H
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Chunlai Wu其他文献

Chunlai Wu的其他文献

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{{ truncateString('Chunlai Wu', 18)}}的其他基金

Wrd promotes active zone stability through dephosphorylation of Coracle
Wrd 通过 Coracle 去磷酸化促进活性区稳定性
  • 批准号:
    10811227
  • 财政年份:
    2023
  • 资助金额:
    $ 18.25万
  • 项目类别:
Enhancing Mask/ANKHD1 activity to protect against Tau-induced neurodegeneration
增强 Mask/ANKHD1 活性以预防 Tau 诱导的神经变性
  • 批准号:
    10288299
  • 财政年份:
    2021
  • 资助金额:
    $ 18.25万
  • 项目类别:
The Role of Highwire/DFsn Ubiquitination Complex During Synaptic Development
Highwire/DFsn 泛素化复合物在突触发育过程中的作用
  • 批准号:
    8467765
  • 财政年份:
    2010
  • 资助金额:
    $ 18.25万
  • 项目类别:
The Role of Highwire/DFsn Ubiquitination Complex During Synaptic Development
Highwire/DFsn 泛素化复合物在突触发育过程中的作用
  • 批准号:
    8271401
  • 财政年份:
    2010
  • 资助金额:
    $ 18.25万
  • 项目类别:
The Role of Highwire/DFsn Ubiquitination Complex During Synaptic Development
Highwire/DFsn 泛素化复合物在突触发育过程中的作用
  • 批准号:
    8066970
  • 财政年份:
    2010
  • 资助金额:
    $ 18.25万
  • 项目类别:
The Role of Highwire/DFsn Ubiquitination Complex During Synaptic Development
Highwire/DFsn 泛素化复合物在突触发育过程中的作用
  • 批准号:
    8672700
  • 财政年份:
    2010
  • 资助金额:
    $ 18.25万
  • 项目类别:
The Role of Highwire/DFsn Ubiquitination Complex During Synaptic Development
Highwire/DFsn 泛素化复合物在突触发育过程中的作用
  • 批准号:
    7944601
  • 财政年份:
    2010
  • 资助金额:
    $ 18.25万
  • 项目类别:

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