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。

基本信息

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(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production.
  • DOI:
    10.1038/s41419-021-04433-w
  • 发表时间:
    2021-12-08
  • 期刊:
  • 影响因子:
    9
  • 作者:
    Zhuravleva V;Vaz-Silva J;Zhu M;Gomes P;Silva JM;Sousa N;Sotiropoulos I;Waites CL
  • 通讯作者:
    Waites CL
Glucocorticoid stress hormones stimulate vesicle-free Tau secretion and spreading in the brain.
糖皮质激素应激激素刺激无囊泡 Tau 蛋白的分泌和在大脑中的扩散。
  • DOI:
    10.21203/rs.3.rs-3097174/v1
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Waites,Clarissa;Yu,Qing;Du,Fang;Belli,Irla;Gomes,Patrícia;Sotiropoulos,Ioannis
  • 通讯作者:
    Sotiropoulos,Ioannis
The synaptic life of microtubules.
  • DOI:
    10.1016/j.conb.2021.03.004
  • 发表时间:
    2021-08
  • 期刊:
  • 影响因子:
    5.7
  • 作者:
    Waites C;Qu X;Bartolini F
  • 通讯作者:
    Bartolini F
Coordination of synaptic vesicle trafficking and turnover by the Rab35 signaling network.
  • DOI:
    10.1080/21541248.2016.1270392
  • 发表时间:
    2019-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Sheehan P;Waites CL
  • 通讯作者:
    Waites CL
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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:
    $ 37.72万
  • 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:
    $ 37.72万
  • 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:
    $ 37.72万
  • 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:
    10364729
  • 财政年份:
    2014
  • 资助金额:
    $ 37.72万
  • 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:
    $ 37.72万
  • 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:
    $ 37.72万
  • 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:
    $ 37.72万
  • 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:
    $ 37.72万
  • 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:
    $ 37.72万
  • 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:
    $ 37.72万
  • 项目类别:
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