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.

项目摘要/摘要 阿尔茨海默氏病和其他tauopathies是影响数百万人的tau蛋白构象疾病。 目前没有手段来根据TAU构象诊断患者。微管相关蛋白 tau可以转化为各种引起不同人类疾病的不同致病形状。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可以在每种疾病中采用。原纤维结构突出了形成淀粉样蛋白基序的核心作用 稳定非极性接触以确定不同的折叠。我们的模型预测了tau的希望 采用结构多晶型物的单体与暴露不同模式的局部结构的扰动有关 淀粉样蛋白原基序。检测tauopathy衍生的tau构象对于发展准确是必不可少的 疾病诊断。为了了解tau淀粉样装配的结构和起源，我们提出了 至：（i）基于功能遗传学的tau结构的预测算法，（ii）局部基序在 控制tau组装的控制，（iii）致病突变在局部结构上的测试作用。我们预计我们的方法 将允许根据premortem中的tau构象的tauopathies进行诊断，并且可能会诊断为预言， 患者样品，还提供了对疾病中tau组装的规则的基本见解。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 项目与NIA的任务保持一致，以支持衰老的生物学和临床研究。