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的病理性聚集和神经原纤维缠结(NFT)或其他包涵体的优势 含有tau是定义阿尔茨海默病(AD)和许多神经退行性疾病的组织病理学特征 统称为tauopathy的疾病。研究的一个主要焦点是对 病理性tau在阿尔茨海默病患者脑神经网络中的传播。尽管我们知道 获得性，tau繁殖所涉及的细胞机制，tau物种参与 传播和准确的播种/模板仍不清楚。考虑到tau的优势作用 在AD和其他疾病的发病机制中的传播，我们进行了无偏的定量质量 基于光谱的研究，以确定参与扩散的特定tau物种和 特别是与这种“牛角种子”相互作用。巴松蛋白(BSN)--突触前活性的大型支架蛋白 区，被确定为从小鼠模型中分离的tau病理种子的重要相互作用因素 以及AD和PSP的尸检样本。先前对AD和PSP患者样本的研究 BSN与两种tauopathy相关。因此，这项建议的主要目的是确定和剖析BSN作为支架的作用机制，以稳定和促进tau病理性种子的传播和神经毒性。通过引入一系列基于生化、分子、组织学、电生理、行为学、成像、生物信息学和质谱学的方法，结合小鼠模型、细胞培养和人死后组织，本建议将1.评估BSN在体内tau发病机制中的作用；2.确定BSN在神经系统中聚集、繁殖和突触毒性的机制基础；3.从一系列不同的tau疾病中检验BSN与tau病理种子的关联是否在人脑中具有菌株特异性。更好地了解牛磺酸种子在病理性牛磺酸种子形成、稳定和繁殖中的作用具有重要意义，因为它可能提供重要信息，有助于我们了解牛磺酸繁殖的机制(S)、参与这一过程的牛磺酸种子的确切性质及其在阿尔茨海默病和其他牛磺酸疾病相关的神经退行性变中的作用。