Tau-seed protein interactome and its role in neurodegenerative tauopathies

Tau 种子蛋白相互作用组及其在神经退行性 tau 病中的作用

• 批准号: 10456475
• 负责人: Cristian Lasagna-Reeves
• 金额: $ 6.93万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456475
• 关键词: Affect; Affinity; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Autopsy; Behavioral; Biochemical; Bioinformatics; Brain; Clinical; Complex; Data Set; Disease; Down-Regulation; Electrophysiology (science); Goals; Heterogeneity; Histologic; Human; Image; Individual; Knowledge; Link; Maintenance; Mass Spectrum Analysis; Medicine; Microfluidics; Microscopy; Modeling; Molecular; Molecular Conformation; Molecular Weight; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathologic; Pathology; Pathway Analysis; Patients; Physiological; Play; Process; Progressive Supranuclear Palsy; Property; Proteins; Proteomics; Reporting; Research; Resolution; Risk Factors; Role; Sampling; Scaffolding Protein; Seeds; Series; Structure; Synapses; Synaptic Vesicles; System; Tauopathies; Testing; Tissues; Work; base; bassoon protein; cytomatrix; genome wide association study; human model; in vivo; loss of function; monomer; mouse model; mutant; neurotoxicity; non-demented; novel; presynaptic; protein aggregation; proteostasis; scaffold; tau Proteins; tau aggregation; tau interaction; transcriptome sequencing

Pathological aggregation of tau and the preponderance of neurofibrillary tangles (NFT) or other inclusions containing tau are defining histopathological features of Alzheimer's disease (AD) and many neurodegenerative diseases collectively known as tauopathies. A major focus of research has been the understanding of the propagation of pathological tau in AD patient brains that follow neuronal networks. Despite the knowledge acquired, the cellular mechanism involved in tau propagation, the nature of the tau species involved in the spreading and the precise seeding/template remains unclear. Considering the preponderant role of tau propagation in the pathogenesis of AD and other tauopathies, we performed an unbiased quantitative Mass Spectrometry based study to determine the specific tau species involved in the spreading and the proteins that specifically interact with this “tau-seed”. Bassoon (BSN), a large scaffolding protein of the presynaptic active zone, was identified as a significant interactor of the tau-pathological-seed isolated from a mouse model for tauopathy, as well as from AD and PSP postmortem samples. Prior research in AD and PSP patient samples have linked BSN with both tauopathies. Therefore, the main goal of this proposal is to determine and dissect the mechanism by which BSN functions as a scaffold to stabilize and facilitate the spreading and neurotoxicity of a tau-pathological-seed. By introducing a series of biochemical, molecular, histological, electrophysiological, behavioral, imaging, bioinformatics and Mass Spectrometry based strategies together with mouse model, cellular culture and human postmortem tissue, this proposal will 1. evaluate the role of BSN in tau pathogenesis in vivo, 2. determine the mechanistic base of BSN in tau aggregation, propagation and synaptotoxicity in neuronal systems and 3. test if BSN's association with tau-pathological-seed is strain specific in human brains from a diverse set of tauopathies. Gaining a better understanding of the contribution of BSN on the formation, stabilization and propagation of a pathological tau-seed is highly significant since it may provide important information that will increase our understanding on the mechanism(s) involved in tau propagation, the precise nature of the tau-seed involved in this process and its role in the neurodegeneration associated to AD and other tauopathies.

tau的病理聚集和神经原纤维缠结（NFT）或其他夹杂物的优势 包含tau是定义阿尔茨海默氏病（AD）和许多神经退行性的组织病理学特征 疾病统称为auopathies。研究的重点是对 遵循神经元网络的AD患者大脑中患者Tau的传播。尽管有知识 获得的，涉及tau繁殖的细胞机制，涉及的tau物种的性质 扩散和精确的播种/模板尚不清楚。考虑tau的优势角色 在AD和其他Tauopath的发病机理中，我们进行了无偏定量质量 基于光谱的研究，以确定与扩散有关的特定tau物种和蛋白质 特别与这种“ tau-seed”互动。巴松（BSN），突触前活性的大脚手架蛋白 区域被确定为从小鼠模型中分离出的tau - 病理种子的重要相互作用者 tauopathy，以及AD和PSP验尸样品。对AD和PSP患者样品的先前研究 将BSN与两种tauopathies联系起来。因此，该提案的主要目标是确定和剖析BSN作为稳定和促进Tau-PARIGATIC-SEDED的扩散和神经毒性的脚手架的机制。通过引入一系列生物化学，分子，组织学，电生理学，行为生理，行为，成像，生物信息学和基于质谱的策略以及小鼠模型，细胞培养和人类后的摩门比组织。神经元系统和3。测试BSN是否与Tau-Phatogary-seed相关性是特定于潜水次痛的人的大脑中的菌株。非常重要地了解BSN对病理tau种子的形成，稳定和传播的贡献非常重要，因为它可能会提供重要的信息，从而增加我们对参与TAU传播的机制的理解，即tau种子的确切性质，与此过程相关的tau-seed与Adurodegeneration与Adurodegeneration与Adurodegeneration相关的作用和与Adurodegeneration相关的作用。