Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
基本信息
- 批准号:10686813
- 负责人:
- 金额:$ 47.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:Adenosine MonophosphateAgingApoptosisAutopsyBiogenesisBiological AssayBrainBrain DiseasesCell DeathCellsClinicalComplexCytosolDataDeacetylationDementia with Lewy BodiesDiagnosisDiseaseDopaminergic CellDown-RegulationExperimental ModelsFibroblastsGeneticGenetic TranscriptionGoalsHealthHeat shock proteinsHumanImpairmentIn VitroIndividualKnockout MiceLewy Body DiseaseMediatingMembrane PotentialsMitochondriaModelingMultiple System AtrophyMutationNeonatalNerve DegenerationNervous SystemNeurodegenerative DisordersNeuronsOrganellesOxidative StressPARK2 genePINK1 genePPAR gammaParkinson DiseasePathogenesisPathogenicityPathologicPathologyPathway interactionsPatientsPharmacotherapyPhosphotransferasesPlayPoint MutationProcessProteinsProteomicsQuality ControlReactive Oxygen SpeciesRoleSignal PathwaySir2-like DeacetylasesSirtuinsTherapeutic InterventionTissuesTransgenic Micealpha synucleinbehavioral phenotypingbiological adaptation to stresscytochrome cexcitotoxicityin vivomitochondrial dysfunctionmutation carrierneuron lossneuroprotectionnew therapeutic targetnoveloverexpressionpharmacologicpreventresponsestable cell linesynucleinopathytargeted treatment
项目摘要
The overall aim of this application is to investigate mechanisms of alpha-synuclein (αsyn)-induced
mitochondrial dysfunction in Lewy body diseases (LBD). Despite its predominant localization in the
cytosol, αsyn localizes to mitochondria in post-mortem LBD brains. Within the mitochondria, αsyn
accumulation can impair complex I and IV function, decrease membrane potential, increase levels of
reactive oxygen species, and increase apoptosis associated with cytochrome c release from the
mitochondria. Together these data suggest an increase in mitochondrial αsyn expression and/or
abnormal accumulation of toxic aggregates interferes with mitochondrial function. Maintaining
mitochondrial health is essential to prevent neuronal cell death in the brain. Sirtuin 3 (SIRT3) is a
NAD+-dependent protein deacetylase exclusively localized to the mitochondria where it regulates
mitochondrial processes including protein deacetylation, organelle biogenesis, and oxidative stress.
SIRT3 is expressed at high levels in the brain and other nervous system tissues, and can act as a pro-
survival factor, playing an essential role in protecting neurons under conditions of excitotoxicity and
rescuing neuronal loss in neurodegenerative models. Experimental evidence indicates that SIRT3-
induced neuroprotection against oxidative stress is partially mediated by enhancement of mitochondrial
biogenesis and integrity. As we consider sirtuin-based drug therapies for diseases of ageing, it is
important to determine if modulating SIRT3 can protect against neurodegeneration where mitochondrial
dysfunction has been demonstrated to play a role. This proposal will investigate how mitochondrial
SIRT3 contributes to αsyn-induced mitochondrial dysfunction in 3 coordinated aims. In aim 1 we will
perform comprehensive mitochondrial function analyses to reveal how αsyn accumulation leads to
mitochondrial damage and the role of SIRT3 therein using patient-derived cells and postmortem brain.
In aim 2 we will interrogate the SIRT3 regulated acetylome to identify novel targets of αsyn-associated
mitochondrial dysfunction, and in aim 3 we will validate SIRT3 as a novel target for therapeutic
intervention in PD in a comprehensive in vivo approach using genetic overexpression and
pharmacological activation. The proposed rigorous analysis of various mitochondrial aspects will
dissect causes from consequences and reveal the cross-talk between αsyn, SIRT3, and mitochondrial
signaling pathways as well as oxidative and protein stress responses.
本应用的总体目的是研究α-突触核蛋白(α-syn)诱导的机制
路易体病(LBD)的线粒体功能障碍。尽管其主要本地化在
胞浆中,αSYN定位于死后LBD脑中的线粒体。在线粒体内,α同步
堆积可损害复合体I和IV的功能,降低膜电位,增加血浆中
活性氧物种,并增加与细胞色素c释放相关的凋亡
线粒体。综上所述,这些数据表明线粒体αSYN表达和/或
有毒聚集体的异常积累干扰了线粒体的功能。维护
线粒体的健康对于防止大脑中的神经细胞死亡至关重要。Sirtuin 3(SIRT3)是一种
NAD+依赖的蛋白脱乙酰酶仅定位于线粒体,在那里它调节
线粒体过程包括蛋白质去乙酰化、细胞器生物发生和氧化应激。
SIRT3在大脑和其他神经系统组织中高水平表达,并可作为一种促进-
存活因子,在兴奋性毒性条件下保护神经元起着至关重要的作用
挽救神经退行性变模型中的神经元丢失。实验证据表明,SIRT3-
氧化应激诱导的神经保护作用部分是通过增强线粒体来实现的
生物发生和完整性。当我们考虑以sirtuin为基础的药物治疗老年病时,它是
重要的是要确定调节SIRT3是否可以保护线粒体所在位置的神经变性
已经证明功能障碍起到了一定的作用。这项提案将研究线粒体是如何
SIRT3在αSYN诱导的线粒体功能障碍中起3个协同作用。在目标1中,我们将
进行全面的线粒体功能分析,揭示αSYN的积累是如何导致
利用患者来源细胞和死后脑研究线粒体损伤和SIRT3在其中的作用。
在目标2中,我们将询问sirt3调控的乙酰组以确定αSYN相关的新靶点
线粒体功能障碍,在目标3中,我们将验证SIRT3作为治疗的新靶点
利用基因过表达和基因治疗的综合体内方法干预帕金森病
药理激活。拟议的对线粒体各个方面的严格分析将
剖析原因和后果,揭示αSYN、SIRT3和线粒体之间的相互作用
信号通路以及氧化和蛋白质应激反应。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cellular models of alpha-synuclein toxicity and aggregation.
- DOI:10.1111/jnc.14806
- 发表时间:2019-09
- 期刊:
- 影响因子:4.7
- 作者:Delenclos M;Burgess JD;Lamprokostopoulou A;Outeiro TF;Vekrellis K;McLean PJ
- 通讯作者:McLean PJ
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Pamela J McLean的其他文献
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{{ truncateString('Pamela J McLean', 18)}}的其他基金
Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
- 批准号:
10409706 - 财政年份:2019
- 资助金额:
$ 47.65万 - 项目类别:
Functional assessment of pathological α-syn and Aβ species in LBD
LBD 中病理 α-syn 和 Aβ 物种的功能评估
- 批准号:
10237303 - 财政年份:2019
- 资助金额:
$ 47.65万 - 项目类别:
Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
- 批准号:
10348483 - 财政年份:2019
- 资助金额:
$ 47.65万 - 项目类别:
Functional assessment of pathological α-syn and Aβ species in LBD
LBD 中病理 α-syn 和 Aβ 物种的功能评估
- 批准号:
10022185 - 财政年份:2019
- 资助金额:
$ 47.65万 - 项目类别:
Functional assessment of pathological α-syn and Aβ species in LBD
LBD 中病理 α-syn 和 Aβ 物种的功能评估
- 批准号:
10478195 - 财政年份:2019
- 资助金额:
$ 47.65万 - 项目类别:
Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
- 批准号:
9753438 - 财政年份:2019
- 资助金额:
$ 47.65万 - 项目类别:
Functional assessment of pathological α-syn and Aβ species in LBD
LBD 中病理 α-syn 和 Aβ 物种的功能评估
- 批准号:
10686906 - 财政年份:2019
- 资助金额:
$ 47.65万 - 项目类别:
Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
- 批准号:
10161872 - 财政年份:2019
- 资助金额:
$ 47.65万 - 项目类别:
Extracellular alpha-synuclein in Parkinson's Disease
帕金森病中的细胞外 α-突触核蛋白
- 批准号:
8234547 - 财政年份:2011
- 资助金额:
$ 47.65万 - 项目类别:
Extracellular alpha-synuclein in Parkinson's Disease
帕金森病中的细胞外 α-突触核蛋白
- 批准号:
8695502 - 财政年份:2011
- 资助金额:
$ 47.65万 - 项目类别:
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