Elucidating Autophagy-lysosome Mechanism in LRRK2 and alpha-synuclein Pathogenic Pathways
阐明 LRRK2 和 α-突触核蛋白致病途径中的自噬溶酶体机制
基本信息
- 批准号:9017208
- 负责人:
- 金额:$ 36.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAffectAnimal ModelAutophagocytosisAutophagosomeAxonBrainCell modelCollaborationsComplexDataDefectDopamineEndosomesExcisionExocytosisGene ExpressionGenesGeneticGenetic screening methodGoalsGuanosine Triphosphate PhosphohydrolasesHomeostasisHumanIn VitroKidneyKnockout MiceKnowledgeLRRK2 geneLinkLysosomesMediatingMembrane Protein TrafficMolecularMolecular GeneticsMusMutationNeuritesNeuronsOrganellesOutcomeParkinson DiseasePathogenesisPathway interactionsPhenocopyPhosphatidylinositolsPhosphotransferasesProcessProtein-Serine-Threonine KinasesProteinsRecyclingRegulationReportingResearchRodentRodent ModelRoleSNAP receptorStructureTestingTherapeuticTransgenic MiceTransgenic Organismsabstractingage relatedagedalpha synucleinbasebiochemical modelexperiencein vivoinjuredinterdisciplinary approachmouse modelmutantneuroprotectionneurotoxicityoverexpressionparkin gene/proteinprotein aggregateprotein transporttraffickingtranscription factortransmission process
项目摘要
Project Summary/Abstract
Our goal is to elucidate autophagy-lysosomal mechanism in the pathogenesis of Parkinson's disease (PD).
Early pathological analysis of PD and recent studies of PD-linked genes, such as SNCA, LRRK2, Parkin,
Pink1, GBA and ATP13A2, implicates dysfunctional autophagy-lysosomal pathway in the pathogenesis of PD.
Recent evidence shows that inhibition of LRRK2 or expression of LRRK2 PD mutants causes aberrant
autophagic activity, but the detailed mechanism is unclear. Our preliminary study suggests a link of LRRK2 to
an autophagy kinase, which is essential for autophagy and required for axon/neurite outgrowth. Here we
propose to investigate the molecular mechanism whereby LRRK2 regulates autophagy through directly
targeting autophagy machinery and dysfunctional autophagy as a potential PD pathogenic pathway. We
previously reported that disruption of autophagy in mice leads to age-dependent accumulation of endogenous
α-Syn in dystrophic axons and altered dopamine transmission, consist with impaired autophagy as one of the
failing cellular mechanisms involved in the pathogenesis of PD. Emerging evidence suggests that autophagy
not only participates in degradation of α-Syn, but also is involved in the secretion pathway of α-Syn, which
underlies the spreading of synucleiopathy. Fibrillar α-Syn can be secreted through exosomes and/or
autophagosome-related structures. Furthermore, increasing autophagy gene beclin1 or transcription factor
TFEB expression facilitates the autophagic clearance of α-Syn and offers neuroprotection in rodent models.
However, the precise mechanism for the autophagic clearance of intracellular α-Syn remains poorly
characterized. Finally, whether LRRK2 also contributes to the control of α-Syn homeostasis through regulation
of autophagy is unclear. Given the emerging role of autophagy in the exocytosis of α-Syn, we hypothesize that
autophagy regulates α-Syn clearance through both degradative and secretory pathways; LRRK2 modulates α-
Syn homeostasis by targeting autophagy. In Project 3 we propose (1) to determine molecular and genetic
basis for LRRK2-mediated autophagy regulation. We will use biochemical, cellular and animal models to
dissect the role for LRRK2 wildtype and PD mutation G2019S in autophagy control through modulating the
autophagy kinase and SNARE-related protein trafficking; (2) to determine the mechanism that autophagy
and LRRK2 modulate α-Syn homeostasis by targeting multiple trafficking pathways. We will apply
multidisciplinary approaches to test that LRRK2 and autophagy pathway converge to regulate α-Syn
homeostasis by targeting secretion and degradation in cell and animal models of PD. Our project 3 will be
conducted in close collaboration with Drs. Jie Shen and Tom Südhof, who have extensive experience in
LRRK2 and α-Syn research, respectively. Completion of our project 3 is expected to provide timely knowledge
for understanding LRRK2 pathogenic mechanism and developing potential therapeutic strategies by targeting
autophagy-lysosome pathways for the clearance of α-synuclein.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Zhenyu Yue其他文献
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{{ truncateString('Zhenyu Yue', 18)}}的其他基金
Deciphering LRRK2 pathophysiology in mediating gut-brain axis of PD using novel genetic mouse models
使用新型遗传小鼠模型解读 LRRK2 介导 PD 肠脑轴的病理生理学
- 批准号:
10284434 - 财政年份:2021
- 资助金额:
$ 36.9万 - 项目类别:
Determining the neuroprotective mechanism for microglial autophagy in Alzheimer's disease
确定阿尔茨海默病中小胶质细胞自噬的神经保护机制
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10581646 - 财政年份:2021
- 资助金额:
$ 36.9万 - 项目类别:
Administrative management of Mount Sinai PD consortium
西奈山PD财团的行政管理
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10284433 - 财政年份:2021
- 资助金额:
$ 36.9万 - 项目类别:
Determining the neuroprotective mechanism for microglial autophagy in Alzheimer's disease
确定阿尔茨海默病中小胶质细胞自噬的神经保护机制
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10430042 - 财政年份:2021
- 资助金额:
$ 36.9万 - 项目类别:
Determining the neuroprotective mechanism for microglial autophagy in Alzheimer's disease
确定阿尔茨海默病中小胶质细胞自噬的神经保护机制
- 批准号:
10213290 - 财政年份:2021
- 资助金额:
$ 36.9万 - 项目类别:
Determining Selective Autophagy Kinase in Modulating Neurotoxicity in Huntington's Disease Model
确定选择性自噬激酶在亨廷顿病模型中调节神经毒性的作用
- 批准号:
10656193 - 财政年份:2020
- 资助金额:
$ 36.9万 - 项目类别:
Determining selective autophagy kinase in modulating neurotoxicity in Huntington's disease model
确定选择性自噬激酶在亨廷顿病模型中调节神经毒性的作用
- 批准号:
10033925 - 财政年份:2020
- 资助金额:
$ 36.9万 - 项目类别:
Determining selective autophagy kinase in modulating neurotoxicity in Huntington's disease model
确定选择性自噬激酶在亨廷顿病模型中调节神经毒性的作用
- 批准号:
10438575 - 财政年份:2020
- 资助金额:
$ 36.9万 - 项目类别:
Determining selective autophagy kinase in modulating neurotoxicity in Huntington's disease model
确定选择性自噬激酶在亨廷顿病模型中调节神经毒性的作用
- 批准号:
10213157 - 财政年份:2020
- 资助金额:
$ 36.9万 - 项目类别:
DISTINCT REGULATION OF AUTOPHAGIC ACTIVITY BY TWO NOVEL PROTEINS
两种新型蛋白质对自噬活性的独特调节
- 批准号:
8361544 - 财政年份:2011
- 资助金额:
$ 36.9万 - 项目类别:
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