Architecture, dynamics and cell-specific behavior of tau condensates

tau 凝聚物的结构、动力学和细胞特异性行为

基本信息

批准号：
10662730
负责人：
Shana Elbaum
金额：
$ 39.19万
依托单位：
ADVANCED SCIENCE RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662730
关键词：
Address Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Animal Model Architecture Behavior Biochemistry Biology Biophysics Cell Lineage Cell physiology Cells Central Nervous System Complement Confusion Detection Disease Environment Etiology Event Fiber Foundations Frontotemporal Dementia Functional disorder Future Gel Goals Image Impaired cognition Impairment Knowledge Lipids Measures Mediating Modeling Molecular Monitor Mutation Myelin Myelin Basic Proteins Myelin Proteins Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Oligodendroglia Oxidative Stress Pathogenicity Pathologic Pathology Pathway interactions Phase Physical condensation Post-Translational Protein Processing Process Property Protein Isoforms Proteins Reporting Research Priority Resolution Role Site Testing United States National Institutes of Health Variant Work biophysical techniques effective therapy human subject interdisciplinary approach mild cognitive impairment myelin biogenesis novel novel therapeutic intervention oligodendrocyte lineage protein aggregation self assembly symposium tau Proteins tau mutation therapeutic target tool white matter change

项目摘要

Abstract/Project Summary The ultimate goal of this proposal is to understand the molecular and cellular substrates of early tau pathology, in order to create the foundation for future therapeutic targets for Alzheimer’s Disease (AD) and Alzheimer’s Disease Related Dementias (ADRD). Tau is a protein, expressed in neurons and oligodendroglial cells, whose aggregation is a pathological hallmark of a wide range of neurodegenerative diseases, including Fronto-Temporal-Dementia (FTD). Mounting evidence shows that the pathogenic process begins long before the detection of neuronal aggregates, with the detection of white matter changes in subjects with mild cognitive impairment, although the underlying pathogenic processes responsible for these changes remain only partially understood. This proposal will directly address this major gap of knowledge in the field, and tackle the major research priority of the 2019 NIH ADRD Summit, to investigate the early events of the disease. We leverage the expertise of the PI in biochemistry and phase separation and that of the co-I in myelin biology, to test the hypothesis that the white matter changes detected at the early stages of ADRD are mediated by misregulation of the condensed state of tau in oligodendrocytes. This hypothesis is motivated by the evidence that: 1) tau can self-assemble into a novel phase-separated condensed state (“condensate”); 2) tau mutations specific for FTD specifically impact tau condensates and 3) that oligodendroglial lineage cells, the myelin-forming cells of the central nervous system, are specific sites of tau-mediated dysfunction at the early stages of the neurodegenerative process. Extensive evidence in human subjects and animal models of FTD identify myelin damage and oligodendroglial dysfunction at the earliest stages of cognitive decline and support a model of neurodegeneration consequent to myelin pathology and occurring long before the detection of aggregates. Here we take an interdisciplinary biophysical and cellular approach that leverages expertise in tau biochemistry and glial biology, in order to test this hypothesis. In aim1 we will develop quantitative metrics for defining tau condensates – a crucial advance necessary for understanding how tau condensates are modulated. In aim 2 we will determine the influence of tau pathological variants and myelin protein and lipids on tau condensate properties. In aim 3 we shall examine the role of endogenously expressed and exogenously uptaken tau and tau variants in oligodendrocyte lineage cells at specific stages of differentiation. Together, results from this work will illuminate the role of tau condensates in oligodendrocytes and further our knowledge of the events occurring at the early stages of tau pathology.

摘要/项目摘要该提案的最终目标是了解早期 tau 的分子和细胞底物病理学，为阿尔茨海默病的未来治疗目标奠定基础 (AD) 和阿尔茨海默病相关痴呆 (ADRD) 是一种蛋白质，在神经元和神经元中表达。少突胶质细胞，其聚集是多种神经退行性疾病的病理标志越来越多的证据表明，额颞叶痴呆 (FTD) 等疾病是致病的。这个过程早在检测神经聚集之前就开始了，检测白质变化在患有轻度认知障碍的受试者中，尽管潜在的致病过程负责这些变化仅被部分理解。该提案将直接解决这一重大差距。领域知识，并解决 2019 年 NIH ADRD 峰会的主要研究优先事项，调查疾病的早期事件。我们利用 PI 在生物化学和相分离方面的专业知识以及 co-I 在髓磷脂方面的专业知识生物学，检验 ADRD 早期检测到的白质变化的假设该假设是由少突胶质细胞中 tau 蛋白凝聚状态的失调介导的。受到以下证据的启发：1) tau 可以自组装成一种新颖的相分离凝聚态（“凝结物”）；2) FTD 特异的 tau 突变特别影响 tau 凝结物，并且 3) 少突胶质细胞系细胞，中枢神经系统的髓磷脂形成细胞，是人类神经退行性过程早期阶段 tau 介导的功能障碍。 FTD 受试者和动物模型最早发现髓磷脂损伤和少突胶质细胞功能障碍认知能力下降的阶段并支持髓磷脂病理导致的神经退行性变模型早在检测到聚集体之前就发生了。在这里，我们采用跨学科的生物物理和细胞方法，利用 tau 蛋白的专业知识生物化学和神经胶质生物学，为了检验这个假设，我们将进行定量研究。定义 tau 凝聚物的指标——理解 tau 凝聚物如何形成所必需的关键进步在目标 2 中，我们将确定 tau 病理变异和髓磷脂蛋白的影响。在目标 3 中，我们将研究内源表达的作用。以及在特定阶段的少突胶质细胞系细胞中外源摄取的 tau 和 tau 变体差异化。总之，这项工作的结果将阐明 tau 凝聚物在少突胶质细胞中的作用，并进一步阐明我们对 tau 病理学早期阶段发生的事件的了解。