BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
基本信息
- 批准号:10269305
- 负责人:
- 金额:$ 43.63万
- 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
- 起止时间:2021-08-15 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AftercareAlzheimer&aposs DiseaseAreaAutophagocytosisAwarenessBCL2 geneBindingClientDNA cassetteDataDendritic SpinesDevelopmentDiseaseEndosomesEnterobacteria phage P1 Cre recombinaseEstersEventFoundationsFunctional disorderGTPase-Activating ProteinsHealthHomeostasisInjectionsInvestigationKineticsLeucineLoxP-flanked alleleLysosomesMaintenanceMediatingMediator of activation proteinMolecularMorphologyMusNeurodegenerative DisordersNeuronsOutcomePathogenesisPathologicPathologyPathway interactionsPatternPhysiological ProcessesPlayPopulationProcessProteinsProteomeProteomicsQuality ControlReactive Oxygen SpeciesRegulationReportingResistanceRoleSignal TransductionSorting - Cell MovementStressStructureSynapsesSystemTamoxifenTertiary Protein StructureTestingVesiclebasehigh resolution imagingin vivoinnovationinsightlive cell imagingmouse modelnoveloptogeneticsoverexpressionpromoterprotein aggregationproteostasisrecruitrepairedtau Proteinstau aggregationtau expressiontau-1trafficking
项目摘要
Protein quality control systems are essential for maintaining neuronal health, with vacuolar dependent pathways
playing a primary role in these systems. The endolysosome system is a major contributor to the maintenance of
the neuronal proteome, and dysfunction of this system occurs early in the pathogenesis of Alzheimer’s disease
(AD) , and likely contributes to the accumulation and mislocalization of tau, which plays a key role in disease
pathogenesis. Recent data provide compelling evidence that the stress responsive, multi-domain protein, Bcl-2-
associated anthogene 3 (BAG3) plays a role in maintaining protein homeostasis and neuronal health. The
expression of BAG3 in specific neuronal populations positively correlates with resistance to the development of
tau pathology in AD. Further, our preliminary data indicate that BAG3 is an upstream regulator of vacuolar
dependent pathways. The UNDERLYING PREMISE of this proposal is that in neurons, BAG3 plays a critical
role in mediating vacuolar dependent pathways, and thus proteostasis and neuronal integrity. The importance
of BAG3 in mediating proteostasis is illustrated by the fact that BAG3 not only plays an important role in protecting
neurons from the accumulation of pathological tau species, but also likely supports synaptic structure.
Nonetheless, our understanding of the mechanisms by which BAG3 regulates vacuolar dependent processes is
very limited. Although previous studies have implicated BAG3 as a mediator of autophagy, we are the first to
present evidence that BAG3 is a regulator of the endolysosome pathway. Further, our preliminary findings
implicate BAG3 as an important modulator of endosomal sorting required for transport (ESCRT) machinery.
BAG3 interacts withTBC1D10B, the primary GTPase activating protein (GAP) for Rab35, which facilitates the
recruitment of the ESCRT machinery and protein clients to the endosome, as well as mediating other vacuolar
dependent processes. The conceptual framework that BAG3 acts upstream of vacuolar pathways through its
regulation of Rab35 activity is novel and innovative. The OVERALL HYPOTHESIS of this proposal is that the
BAG3-TBC1D10B-Rab35 signaling axis regulates endosome-lysosome function and neuronal health. In
the context of this overall hypothesis the specific aims of this proposal are: to test the hypotheses that: (1) the
BAG3-TBC1D10B-Rab35 signaling axis regulates ESCRT and the endolysosome pathway, (2) in vivo BAG3
and Rab35 coordinate to mediate neuronal ESCRT/vacuolar processes, and contribute to the maintenance
synaptic integrity, and (3) the BAG3-TBC1D10B-Rab35 axis plays a critical role in regulating the clearance of
pathological tau species. These studies will be carried out using mouse models and primary neuron cultures.
The IMPACT of these studies is that they will provide crucial new insights into the mechanisms by which BAG3
acts as an upstream mediator of the endolysosome systems to maintain a healthy neuron. Overall these studies
represent a new, unexplored area of investigation that will increase our understanding of the factors that are
essential to maintain a healthy, functional neuronal proteome.
蛋白质质量控制系统是维持神经元健康的关键,它具有空泡依赖的通路。
在这些系统中扮演主要角色。内溶酶体系统是维持血吸虫病的主要因素
神经元蛋白质组和这个系统的功能障碍在阿尔茨海默病的发病机制中早期就发生了
(AD),并可能导致tau的积累和错误定位,tau在疾病中起关键作用
发病机制。最近的数据提供了令人信服的证据表明,应激反应,多结构域蛋白,Bcl-2-
相关花色基因3(BAG3)在维持蛋白质动态平衡和神经元健康方面起着重要作用。这个
BAG3在特定神经元群体中的表达与对发育的抵抗呈正相关
阿尔茨海默病的tau病理。此外,我们的初步数据表明,BAG3是液泡的上游调节因子
依赖的路径。这一提议的基本前提是,在神经元中,BAG3发挥着关键的作用
在调节空泡依赖通路中的作用,从而调节蛋白平衡和神经元的完整性。它的重要性
BAG3不仅在保护蛋白质的过程中起重要作用,而且在蛋白稳态中起重要作用。
神经细胞由病理性tau种积累而来,也可能支持突触结构。
尽管如此,我们对BAG3调节液泡依赖过程的机制的理解是
非常有限。尽管之前的研究已经将BAG3作为自噬的中介,但我们是第一个
目前有证据表明,BAG3是内溶酶体途径的调节因子。此外,我们的初步调查结果
提示BAG3是运输所需的内体分选(ESCRT)机械的重要调节因子。
BAG3与TbC1D10B相互作用,TbC1D10B是Rab35的主要GTP酶激活蛋白,这有助于
ESCRT机制和蛋白质客户的招募到内体,以及调节其他液泡
从属进程。BAG3通过其作用于空泡通路上游的概念框架
对Rab35活性的调控是新颖和创新的。这项提议的总体假设是
BAG3-TBC1D10B-Rab35信号轴调节内体-溶酶体功能和神经元健康。在……里面
这一总体假设的背景这项建议的具体目的是:检验以下假设:(1)
BAG3-TBC1D10B-Rab35信号轴调节ESCRT和内切酶途径,(2)体内BAG3
和Rab35协调介导神经元ESCRT/空泡过程,并参与维持
突触完整性;(3)BAG3-TBC1D10B-Rab35轴在调节突触清除中起关键作用。
病态的tau物种。这些研究将使用小鼠模型和原代神经元培养进行。
这些研究的影响在于,它们将为BAG3通过何种机制提供至关重要的新见解
作为内溶酶体系统的上游介质,以维持健康的神经元。总体而言,这些研究
代表了一个新的、未探索的调查领域,这将增加我们对以下因素的理解
维持一个健康的、功能正常的神经元蛋白质组所必需的。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Gail V. W. Johnson其他文献
Glycogen Synthase Kinase 3β Phosphorylates Tau at Both Primed and Unprimed Sites
糖原合酶激酶 3β 在引发和未引发的位点磷酸化 Tau
- DOI:
- 发表时间:
2003 - 期刊:
- 影响因子:4.8
- 作者:
Jae;Gail V. W. Johnson - 通讯作者:
Gail V. W. Johnson
Metal-catalyzed oxidation of bovine neurofilaments in vitro.
牛神经丝的体外金属催化氧化。
- DOI:
- 发表时间:
1995 - 期刊:
- 影响因子:7.4
- 作者:
Juan C. Troncoso;Anthony C. Costello;James H. Kim;Gail V. W. Johnson - 通讯作者:
Gail V. W. Johnson
Gail V. W. Johnson的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Gail V. W. Johnson', 18)}}的其他基金
Mitochondrial dysfunction and tau pathology in Alzheimer's disease
阿尔茨海默病中的线粒体功能障碍和 tau 病理学
- 批准号:
10805120 - 财政年份:2023
- 资助金额:
$ 43.63万 - 项目类别:
Mechanisms of Transglutaminase 2 (TG2)-Mediated Gene Expression in Astrocyte
星形胶质细胞中转谷氨酰胺酶 2 (TG2) 介导的基因表达机制
- 批准号:
10293984 - 财政年份:2021
- 资助金额:
$ 43.63万 - 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
- 批准号:
10461933 - 财政年份:2021
- 资助金额:
$ 43.63万 - 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
- 批准号:
10667539 - 财政年份:2021
- 资助金额:
$ 43.63万 - 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
- 批准号:
10374933 - 财政年份:2020
- 资助金额:
$ 43.63万 - 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
- 批准号:
10188394 - 财政年份:2020
- 资助金额:
$ 43.63万 - 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
- 批准号:
10601125 - 财政年份:2020
- 资助金额:
$ 43.63万 - 项目类别:
Tau protein turnover and mitochondrial stress responses
Tau 蛋白周转和线粒体应激反应
- 批准号:
9761421 - 财政年份:2018
- 资助金额:
$ 43.63万 - 项目类别: