Structural and functional characterization of ATP synthase c-subunit leak channel and its role in AD pathogenesis
ATP合酶c亚基泄漏通道的结构和功能特征及其在AD发病机制中的作用
基本信息
- 批准号:10214094
- 负责人:
- 金额:$ 15.81万
- 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:2021-05-15 至 2022-01-01
- 项目状态:已结题
- 来源:
- 关键词:AffinityAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAmyloid beta-ProteinArchitectureBindingBiologyBrainCalciumCell DeathCell Death InductionCell SurvivalCellsCleaved cellComplexCryo-electron tomographyCryoelectron MicroscopyDetergentsDevelopmentEnergy MetabolismEnvironmentEventFunctional disorderGlutamatesGoalsHippocampus (Brain)HumanImmobilizationIn SituIndividualInner mitochondrial membraneInterferometryKineticsLipidsLiposomesLiteratureMeasuresMembraneMitochondriaMitochondrial Proton-Translocating ATPasesModelingMolecularMolecular ConformationMusN-terminalNeurodegenerative DisordersNeuronsOligomycinsOuter Mitochondrial MembranePathogenesisPathologicPathway interactionsPermeabilityPharmacologyPlayPrevention strategyPropertyProteinsReportingResearchResolutionRoleRuptureSignal TransductionStructureSynapsesSystemTestingToxic effectTransgenic Micecyclophilin Dcytochrome cdriving forceinhibitor/antagonistmitochondrial dysfunctionmitochondrial membranemitochondrial permeability transition poremonomermouse modelnanodisknovelnovel therapeuticsoverexpressionparticlepatch clamppreventreconstitutionsensortime use
项目摘要
Abstract
Mitochondrial and synaptic dysfunction are early pathological features and a driving force of
Alzheimer's disease (AD) pathology. Aβ is found to accumulate abnormally in the brains of AD
individuals and in an AD mouse models leading to mitochondrial Ca2+ overload and activation of
mitochondrial permeability transition pore (mPTP). Prolonged opening of mPTP triggers outer
mitochondrial membrane rupture, release of cytochrome c and activation of downstream cell
death pathways. The mPTP has been at the center of extensive scientific research for the last
several decades but it still remains as one of the most mysterious phenomena in biology today
due to its controversial molecular composition and the lack of structural information of its pore.
We have recently demonstrated the novel role of ATP synthase c-subunit ring in forming the
channel of mPTP. Nevertheless, the gating mechanism of the ATP synthase c-subunit leak
channel and conformational changes initiating its opening are yet to be discovered.
In this proposal, we will use single-particle cryo-electron microscopy (cryo-EM) to identify the high-
resolution structure and the open conformation of ATP synthase leak channel in the presence of
channel modulators. We will also perform in situ structural analysis of ATP synthase in its
functional environment within the Aβ-exposed primary hippocampal neurons and in mitochondria
isolated from the mouse models of AD by using cryo-electron tomography (cryo-ET). In this project
we will also investigate the direct role of ATP synthase leak channel as a novel cell death pathway
in AD pathogenesis; we will test whether the pharmacological inhibition of this channel will rescue
neurons from Aβ-induced cell death. Successful completion of this proposal will reveal the
molecular mechanism(s) of mitochondrial permeability transition, the atomic structure of ATP
synthase leak channel, and will aid in the development of new treatments for AD, targeting ATP
synthase.
摘要
线粒体和突触功能障碍是早期的病理特征和驱动力
阿尔茨海默病(AD)病理学。阿尔茨海默病患者大脑中β异常积聚
个体和AD小鼠模型导致线粒体钙超载和激活
线粒体通透性转换孔(MPTP)。MPTP长时间打开触发外部
线粒体膜破裂、细胞色素c释放及下游细胞活化
死亡之路。在过去的几年里,MPTP一直是广泛科学研究的中心
但它仍然是当今生物学中最神秘的现象之一
由于其分子组成存在争议,且缺乏其孔道的结构信息。
我们最近证明了三磷酸腺苷合成酶c亚单位环在形成
MPTP频道。然而,三磷酸腺苷合成酶c亚基泄漏的门控机制
启动其开放的水道和构象变化尚未被发现。
在这项提案中,我们将使用单粒子冷冻电子显微镜(Cryo-EM)来识别高密度的
三磷酸腺苷合酶泄漏通道的拆分结构和开放构象
频道调制器。我们还将对ITS中的ATP合成酶进行原位结构分析
暴露于A-β的原代海马神经元和线粒体内的功能环境
用冷冻电子断层扫描(CRYO-ET)从AD小鼠模型中分离。在这个项目中
我们还将研究ATP合成酶泄漏通道作为一种新的细胞死亡途径的直接作用
在AD的发病机制中,我们将测试该通道的药物抑制是否会挽救
来自β诱导的细胞死亡的神经元。成功完成这项提案将揭示
线粒体通透性转换的分子机制--三磷酸腺苷的原子结构(S)
合成酶泄漏通道,并将有助于开发针对ATP的AD新疗法
合成酶。
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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Nelli Mnatsakanyan其他文献
Nelli Mnatsakanyan的其他文献
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{{ truncateString('Nelli Mnatsakanyan', 18)}}的其他基金
Structural and functional characterization of ATP synthase c-subunit leak channel and its role in AD pathogenesis
ATP合酶c亚基泄漏通道的结构和功能特征及其在AD发病机制中的作用
- 批准号:
10553483 - 财政年份:2021
- 资助金额:
$ 15.81万 - 项目类别:
Molecular components of the mitochondrial permeability transition pore and its role in neurodegenerative diseases
线粒体通透性转换孔的分子组成及其在神经退行性疾病中的作用
- 批准号:
10553396 - 财政年份:2017
- 资助金额:
$ 15.81万 - 项目类别:
Molecular components of the mitochondrial permeability transition pore and its role in neurodegenerative diseases
线粒体通透性转换孔的分子组成及其在神经退行性疾病中的作用
- 批准号:
9905337 - 财政年份:2017
- 资助金额:
$ 15.81万 - 项目类别:














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