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: 10470271
• 负责人: Cristian Lasagna-Reeves
• 金额: $ 70.47万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470271
• 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 蛋白的病理性聚集以及神经原纤维缠结 (NFT) 或其他包涵体的优势 含有 tau 蛋白的蛋白质定义了阿尔茨海默病 (AD) 和许多神经退行性疾病的组织病理学特征 统称为tau蛋白病的疾病是研究的一个主要焦点。 尽管有相关知识，AD 患者大脑中病理性 tau 蛋白仍遵循神经网络的传播。 获得性、参与 tau 增殖的细胞机制、参与 Tau 增殖的 tau 物种的性质 考虑到 tau 蛋白的主导作用，传播和精确的播种/模板仍不清楚。 为了了解 AD 和其他 tau 病发病机制中的传播，我们进行了无偏定量 Mass 基于光谱测定的研究，以确定参与传播的特定 tau 物种和蛋白质 与这种“tau 种子”（BSN）（一种突触前活性的大支架蛋白）发生特异性相互作用。 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因子 tau 蛋白病以及 AD 和 PSP 死后样本的先前研究表明。 因此，该提案的主要目标是通过引入一系列生化物质来确定和剖析 BSN 作为支架稳定和促进 tau 病理种子的扩散和神经毒性的机制。 、分子、组织学、电生理学、行为、成像、生物信息学和基于质谱的策略以及小鼠模型、细胞培养和人类死后组织，该提案将 1. 评估BSN 在体内 tau 发病机制中的作用，2. 确定 BSN 在神经元系统中 tau 聚集、传播和突触毒性中的机制基础，3. 测试 BSN 与 tau 病理种子的关联是否在来自不同 tau 病的人脑中具有菌株特异性更好地了解 BSN 对病理 tau 种子的形成、稳定和传播的贡献。非常重要，因为它可能提供重要信息，增加我们对 tau 传播机制、参与该过程的 tau 种子的精确性质及其在 AD 和其他 tau 病相关神经变性中的作用的理解。