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对维持神经元健康至关重要,具有液泡依赖途径
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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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
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{{ 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: