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: 10683165
• 负责人: Cristian Lasagna-Reeves
• 金额: $ 63.76万
• 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/10683165
• 关键词: Acceleration; Affect; Affinity; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Autophagocytosis; Autopsy; Behavioral; Biochemical; Bioinformatics; Brain; Clinical; Complex; Data Set; Disease; Down-Regulation; Electrophysiology (science); Goals; Heterogeneity; Histologic; Human; Image; Individual; Knowledge acquisition; Link; Maintenance; Mass Spectrum Analysis; Medicine; Microfluidics; 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; Risk Factors; Role; Sampling; Scaffolding Protein; Series; Structure; Synapses; Synaptic Vesicles; Syndrome; System; Tauopathies; Testing; Tissues; Work; base; bassoon protein; cytomatrix; genome wide association study; human model; in vivo; loss of function; monomer; mouse model; mutant; neuropathology; neurotoxicity; non-demented; novel; presynaptic; protein aggregation; proteostasis; scaffold; superresolution microscopy; 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蛋白的病理性聚集和神经纤维缠结（NFT）或其他内含物的优势 含有tau的蛋白质是阿尔茨海默病（AD）和许多神经退行性疾病的定义性组织病理学特征。 统称为tau蛋白病的疾病。研究的一个主要焦点是了解 AD患者脑中病理性tau的传播遵循神经元网络。尽管知道 获得性，涉及tau传播的细胞机制，涉及tau种类的性质， 传播和精确的接种/模板仍然不清楚。考虑到tau蛋白的优势作用， 传播在AD和其他tau蛋白病的发病机制，我们进行了无偏定量质量 基于光谱的研究，以确定参与传播的特定tau种类和 特别是与这种“tau种子”相互作用。巴松管（BSN），突触前活性的大支架蛋白， 区，被鉴定为从小鼠模型中分离的tau-病理-种子的显著相互作用物， tau蛋白病，以及从AD和PSP尸检样品。先前对AD和PSP患者样本的研究 BSN与两种tau蛋白病有关因此，本提案的主要目标是确定和剖析BSN作为支架发挥作用以稳定和促进tau病理种子的扩散和神经毒性的机制。通过介绍一系列基于生物化学、分子生物学、组织学、电生理学、行为学、影像学、生物信息学和质谱分析的策略，以及小鼠模型、细胞培养和人类死后组织，本提案将1.评估BSN在体内tau发病机制中的作用，2.确定BSN在神经元系统中的tau聚集、传播和突触毒性中的机制基础，以及3.测试BSN与tau病理种子的关联是否在来自不同的tau病变组的人脑中是菌株特异性的。更好地理解BSN对病理性tau种子的形成、稳定和传播的贡献是非常重要的，因为它可以提供重要的信息，这些信息将增加我们对tau传播中涉及的机制、该过程中涉及的tau种子的确切性质及其在与AD和其他tau蛋白病相关的神经变性中的作用的理解。

项目成果

Pathological tau and reactive astrogliosis are associated with distinct functional deficits in a mouse model of tauopathy.

• DOI: 10.1016/j.neurobiolaging.2021.09.006
• 发表时间: 2022-01
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Patel H;Martinez P;Perkins A;Taylor X;Jury N;McKinzie D;Lasagna-Reeves CA
• 通讯作者: Lasagna-Reeves CA

Bassoon contributes to tau-seed propagation and neurotoxicity.

• DOI: 10.1038/s41593-022-01191-6
• 发表时间: 2022-12
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Martinez, Pablo;Patel, Henika;You, Yanwen;Jury, Nur;Perkins, Abigail;Lee-Gosselin, Audrey;Taylor, Xavier;You, Yingjian;Di Prisco, Gonzalo Viana;Huang, Xiaoqing;Dutta, Sayan;Wijeratne, Aruna B.;Redding-Ochoa, Javier;Shahid, Syed Salman;Codocedo, Juan F.;Min, Sehong;Landreth, Gary E.;Mosley, Amber L.;Wu, Yu-Chien;McKinzie, David L.;Rochet, Jean-Christophe;Zhang, Jie;Atwood, Brady K.;Troncoso, Juan;Lasagna-Reeves, Cristian A.
• 通讯作者: Lasagna-Reeves, Cristian A.

The reduction of astrocytic tau prevents amyloid-β-induced synaptotoxicity.

• DOI: 10.1093/braincomms/fcac235
• 发表时间: 2022
• 期刊: Brain communications
• 影响因子: 4.8

Activated endothelial cells induce a distinct type of astrocytic reactivity.

• DOI: 10.1038/s42003-022-03237-8
• 发表时间: 2022-03-29
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Taylor X;Cisternas P;Jury N;Martinez P;Huang X;You Y;Redding-Ochoa J;Vidal R;Zhang J;Troncoso J;Lasagna-Reeves CA
• 通讯作者: Lasagna-Reeves CA