Seeds and Strains Derived from Tau Monomer - Perez Diversity Supplement

Tau 单体衍生的种子和菌株 - Perez Diversity Supplement

• 批准号: 10300865
• 负责人: MARC I DIAMOND
• 金额: $ 6.47万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300865
• 关键词: Alzheimer' s Disease; Animal Model; Biosensor; Brain; Cells; Clinical; Cryoelectron Microscopy; Data; Diagnostic; Disease; Disease Progression; Growth; Human; Individual; Mass Spectrum Analysis; Molecular Conformation; Neurons; Pathology; Pattern; Publications; Seeds; Structure; Tauopathies; Testing; Therapeutic; Work; accurate diagnosis; base; brain cell; crosslink; molecular modeling; monomer; neuropathology; personalized medicine; structural biology; tau Proteins; tau aggregation

PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) and related tauopathies are major diagnostic, therapeutic, and clinical challenges. Our previous work suggest that different tauopathies are based on unique tau aggregate conformations, or “strains,” and that strain identity predicts specific disease progression patterns in animal models. We hypothesize that distinct, self-propagating tau strains can move between cells of the brain to propagate pathology in humans. Recent publications from our group indicate that tau monomer in fact encodes strains. However this has not been rigorously tested across tauopathies. We will test this idea first by determining whether tau monomer encodes the same sets of strains encoded by larger assemblies in human brain (Aim 1). Next we will use multiplex biosensors to classify monomer from human tauopathies, and determine whether monomer can classify individuals in correlation with neuropathology with the same fidelity as larger assemblies. We will also test the fidelity of strain propagation in human neurons vs. HEK293 cells in comparison those strains isolated directly from human brain (Aim 2). Finally, we use structural biology approaches to determine the conformations of seed-competent monomer. In particular, we will determine whether local structures in tau predict its subsequent assembly into fibrils. This will be based on crosslinking mass spectrometry, molecular modeling, cryoEM, and microcrystallography. We predict that tau monomer will encode strain composition across tauopathies. If we are successful, we anticipate ultimately that it will be possible to classify tauopathies based on the conformation with tau monomer. This could have important implications for accurate diagnosis and personalized therapy.

项目总结/摘要 阿尔茨海默病（AD）和相关的Tau蛋白病是阿尔茨海默病的主要诊断、治疗和临床治疗疾病。 挑战我们以前的工作表明，不同的tau蛋白病是基于独特的tau蛋白聚集体 构象，或“菌株”，并且菌株身份预测特定的疾病进展模式， 动物模型我们假设，不同的，自我繁殖的tau蛋白株可以在细胞之间移动， 大脑在人类中传播病理学。我们小组最近的出版物表明， 单体实际上编码菌株。然而，这尚未在tau蛋白病中进行严格测试。 我们将首先通过确定tau单体是否编码相同的菌株集来验证这一想法 由人脑中较大的组件编码（目标1）。接下来，我们将使用多重生物传感器， 从人类tau蛋白病分类单体，并确定单体是否可以分类个体 与神经病理学相关，具有与较大组件相同的保真度。我们还将测试 与那些分离的菌株相比，菌株在人神经元与HEK 293细胞中繁殖的保真度 直接来自人脑（目标2）。最后，我们使用结构生物学方法来确定 种子感受态单体的构象。特别是，我们将确定当地的结构是否 预测其随后组装成原纤维。这将基于交联质量 光谱学、分子建模、cryoEM和微晶学。我们预测tau单体 将编码tau蛋白病的菌株组成。如果我们成功了，我们预计最终 将有可能基于与tau单体的构象对tau蛋白病进行分类。这本可以 这对准确诊断和个性化治疗具有重要意义。

项目成果

DnaJC7 specifically regulates tau seeding.

• DOI: 10.7554/elife.86936
• 发表时间: 2023-06-30
• 期刊: eLife
• 影响因子: 7.7
• 作者: Perez VA;Sanders DW;Mendoza-Oliva A;Stopschinski BE;Mullapudi V;White CL;Joachimiak LA;Diamond MI
• 通讯作者: Diamond MI

The interactions that shape amyloid fibrils in disease.

疾病中形成淀粉样原纤维的相互作用。

• DOI: 10.1016/j.str.2022.07.003
• 发表时间: 2022
• 期刊: Structure (London, England : 1993)
• 作者: Joachimiak,LukaszA

Seed-competent tau monomer initiates pathology in a tauopathy mouse model.

• DOI: 10.1016/j.jbc.2022.102163
• 发表时间: 2022-08
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Mirbaha, Hilda;Chen, Dailu;Mullapudi, Vishruth;Terpack, Sandi Jo;White, Charles L.;Joachimiak, Lukasz A.;Diamond, Marc, I
• 通讯作者: Diamond, Marc, I