Structural profiling of tauopathy seeds

tau蛋白病种子的结构分析

• 批准号: 10585846
• 负责人: Lukasz A. Joachimiak
• 金额: $ 123万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585846
• 关键词: Address; Adopted; Age; Aging; Alanine; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Amino Acids; Amyloid; Binding; Biological Assay; Biophysics; Brain; Cells; Clinical Research; Collaborations; Cryoelectron Microscopy; Dementia; Deposition; Detection; Diagnosis; Diagnostic; Diamond; Disease; Doctor of Medicine; Elements; Genetic; Goals; In Vitro; Individual; Link; MAPT gene; Mass Spectrum Analysis; Methods; Microtubules; Mission; Modeling; Molecular; Molecular Conformation; Mutagenesis; Mutation; Neurodegenerative Disorders; Nuclear Magnetic Resonance; Pathogenicity; Patients; Pattern; Peptides; Persons; Polymorph; Prevalence; Protein Conformation; Recombinants; Resistance; Resolution; Role; Sampling; Scanning; Shapes; Site; Source; Structure; Tauopathies; Testing; Therapeutic; Variant; Work; amyloid formation; biological research; crosslink; design; disease diagnosis; experimental study; human disease; in silico; in vitro Assay; insight; mind control; molecular dynamics; monomer; prediction algorithm; predictive modeling; prevent; self assembly; tau Proteins; tau aggregation; tau conformation; tau mutation; therapy development; tool

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease and other tauopathies are tau protein conformation diseases that impact millions of people. There is currently no means to diagnose patients based on tau conformation. The microtubule associated protein tau can convert into distinct pathogenic shapes each causing different human diseases. High-resolution cryo- Electron Microscopy structures of tau fibrils isolated from different diseases reveal the diversity of structures that tau can adopt in each disease. Fibril structures highlight the central role of amyloidogenic motifs forming stabilizing nonpolar contacts to determine the distinct folds. Our model predicts that the propensity of a tau monomer to adopt structural polymorphs is linked to perturbation of local structures that expose different patterns of amyloidogenic motifs. Detection of tauopathy-derived tau conformations will be essential to develop accurate disease diagnoses. To understand the structure and origins of tau amyloid assembly in tauopathies, we propose to: (i) develop predictive algorithms for tau structure based on functional genetics, (ii) test role of local motifs in control of tau assembly, (iii) test role of pathogenic mutations on local structure. We anticipate that our approach will allow diagnosis of tauopathies based on tau conformation in premortem, and possibly presymptomatic, patients samples, and also provide fundamental insight into the rules that govern tau assembly in disease. Our long-term goal is to develop diagnostic and therapeutic approaches to treat neurodegenerative diseases. This project is in alignment with the mission of the NIA to support biological and clinical research on aging.

项目概要/摘要 阿尔茨海默病和其他 tau 蛋白病是影响数百万人的 tau 蛋白构象疾病。 目前尚无根据 tau 构象诊断患者的方法。微管相关蛋白 tau 蛋白可以转化为不同的致病形状，每种致病形状都会导致不同的人类疾病。高分辨率冷冻 从不同疾病中分离出的 tau 原纤维的电子显微镜结构揭示了结构的多样性 tau蛋白可以应用于每种疾病。原纤维结构突出了淀粉样蛋白形成基序形成的核心作用 稳定非极性接触以确定不同的折叠。我们的模型预测 tau 的倾向 单体采用结构多晶型物与暴露不同模式的局部结构的扰动有关 淀粉样蛋白生成基序。检测 tau 蛋白病衍生的 tau 构象对于开发准确的 疾病诊断。为了了解 tau 蛋白病中 tau 淀粉样蛋白组装的结构和起源，我们建议 目的：（i）开发基于功能遗传学的 tau 结构预测算法，（ii）测试局部基序在 tau 组装的控制，(iii) 测试致病突变对局部结构的作用。我们预计我们的方法 将允许根据死前和可能症状前的 tau 构象诊断 tau 病， 患者样本，还提供了对疾病中控制 tau 蛋白组装规则的基本见解。我们的 长期目标是开发治疗神经退行性疾病的诊断和治疗方法。这 该项目符合 NIA 支持衰老生物学和临床研究的使命。