J-domain protein conformational selectivity for tau in disease

Tau是一种微管相关蛋白，可以从健康的形状转化为富含β-折叠的淀粉样蛋白。 阿尔茨海默氏症和其他20多种相关肌萎缩症的基础结构。最近的低温- 不同类型颈椎病患者的tau原纤维的EM结构显示出结构多态 这将每个肌萎缩症与不同的淀粉样蛋白结构联系在一起。J结构域蛋白(JDP)分子伴侣家族 在调节tau功能以减轻疾病中淀粉样蛋白聚集方面发挥核心作用。多元化的家庭如何 JDP分子伴侣区分结合不同的tau构象仍然知之甚少。我的实验室 对调节tau聚集的因素进行了CRISPR基因敲除筛选，并确定了两个JDP， Dna JC7和Dna JB6。在最近发表的Work中，我们揭示了Dna JC7增强了对 与易于聚集的突变体或致病种子相比，天然折叠的野生型tau。我们假设 不同的JDP家族编码对不同构象底物的选择性。我们的数据显示 JDP调节tau聚集的新机制可以作为一种诊断和一种 治疗性干预。有几个重要的问题仍然存在。与tau绑定的JDP是如何歧视的 不同的tau构象？JDPs能在体内改变tau的病理吗？在这项提案中，我们的目标是定义一个 在体外，JDP的子集识别与细胞中不同的tau病理相关的tau的不同构象 在活体内。我们将首先使用生化和细胞方法来了解JPD是如何识别不同的 Tau的构象。我们还将确定tau与Dna JC7和Dna JB6的络合物的结构。最后， 我们将在体内检测Dna JC7和Dna JB6在tau病理发展过程中的活性。我们的长期目标 是开发可以减少淀粉样蛋白沉积和减缓神经退化的疗法。该项目正在进行中 与NIA支持衰老生物学和临床研究的使命保持一致。

Tau is a microtubule-associated protein that converts from a healthy shape into beta-sheet rich amyloid structures which underlie pathology in Alzheimer’s disease and over 20 other related tauopathies. Recent cryo- EM structures of tau fibrils derived from different tauopathy patient samples reveal structural polymorphisms that link each tauopathy to distinct amyloid structures. The J-domain protein (JDP) molecular chaperone family play a central role in regulating tau function to mitigate amyloid assembly in disease. How the diverse family of JDP molecular chaperones discriminate binding different tau conformations remains poorly understood. My lab employed a CRISPR knock-out screen for factors that regulate tau aggregation and identified two JDPs, DnaJC7 and DnaJB6. In recently published worked, we revealed that DnaJC7 has enhanced specificity for natively folded wild-type tau compared to aggregation-prone mutants or pathogenic seeds. We hypothesize that the diverse JDP family encodes selectivity for different conformations of substrates. Our data suggests that novel mechanisms of JDP regulation of tau aggregation could be exploited as both a diagnostic and a therapeutic intervention. Several important questions remain. How do JDPs that bind to tau discriminate different tau conformations? Can JDPs modify tau pathology in vivo? In this proposal, we aim to define how a subset of JDPs recognize different conformations of tau linked to different tau pathologies in cells, in vitro and in vivo. We will first use biochemical and cellular approaches to understand how JPDs recognize different conformations of tau. We will also determine structures of tau in complex with DnaJC7 and DnaJB6. Finally, we will test the activity of DnaJC7 and DnaJB6 on the development of tau pathology in vivo. Our long-term goal is to develop therapies that can reduce amyloid deposition and slow neurodegeneration. This project is in alignment with the mission of the NIA to support biological and clinical research on aging.