Architecture, dynamics and cell-specific behavior of tau condensates

摘要/项目摘要 这项提议的最终目标是了解早期tau的分子和细胞底物。 病理学，为阿尔茨海默病未来的治疗目标奠定基础 (AD)和阿尔茨海默病相关痴呆(ADRD)。Tau是一种蛋白质，在神经元和 少突胶质细胞，其聚集是广泛的神经退行性变的病理特征 疾病，包括额颞性痴呆(FTD)。越来越多的证据表明， 这一过程早在检测到神经元聚集体之前就开始了，检测到白质的变化 在轻度认知障碍的受试者中，尽管潜在的致病过程负责 人们对这些变化只有部分了解。这项提议将直接解决这一重大差距 该领域的知识，并解决2019年NIH ADRD峰会的主要研究重点，以 调查疾病的早期事件。 我们利用了PI在生物化学和相分离方面的专业知识，以及髓鞘中co-I的专业知识 生物学，以检验在ADRD早期阶段检测到的白质变化是 由少突胶质细胞中tau凝聚状态的错误调节所介导。这一假设是 其动机是：1)tau可以自组装成一种新的相分离凝聚态 (“冷凝物”)；2)FTD特有的tau突变专门影响tau冷凝物；3) 少突胶质系细胞是中枢神经系统的髓鞘形成细胞，是 Tau介导的神经退变过程早期阶段的功能障碍。在人类身上有大量证据 FTD的受试者和动物模型最早确定髓鞘损伤和少突胶质细胞功能障碍 认知衰退的阶段，并支持髓鞘病理和神经退行性变的模型 远在检测到聚集体之前很久就发生的。 在这里，我们采用跨学科的生物物理和细胞方法，利用tau的专业知识。 生物化学和神经胶质生物学，以验证这一假说。在AIM 1中，我们将制定量化 定义焦油凝析油的度量标准--理解焦油凝析油如何凝结的关键进展 都是调制的。在目标2中，我们将确定tau病理变异和髓鞘蛋白的影响。 和脂类对牛磺酸凝析油性质的影响。在目标3中，我们将研究内源性表达的作用 并在特定阶段的少突胶质细胞系细胞中外源性摄取tau和tau变体 差异化。 总之，这项工作的结果将阐明tau凝聚体在少突胶质细胞中的作用，并进一步 我们对发生在tau病理早期阶段的事件的了解。

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.