J-domain protein conformational selectivity for tau in disease

Tau是一种微管相关蛋白，可从健康的形状转化为富含β折叠的淀粉样蛋白 这些结构是阿尔茨海默病和20多种其他相关tau蛋白病的病理基础。最近的低温- 来源于不同tau蛋白病患者样品的tau原纤维的EM结构揭示了结构多态性 将每种tau蛋白病与不同的淀粉样结构联系起来。J结构域蛋白（JDP）分子伴侣家族 在调节tau蛋白功能以减轻疾病中的淀粉样蛋白组装中发挥核心作用。多元化的家庭 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 采用CRISPR敲除筛选调节tau聚集的因子并鉴定了两种JDP， DnaJC 7和DnaJB 6。在最近发表的工作中，我们揭示了DnaJC 7增强了对 与聚集倾向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。我们的数据表明 JDP调节tau蛋白聚集的新机制可以作为诊断和治疗的一种手段。 治疗干预还有几个重要问题。与tau蛋白结合的JDP如何区分 不同的tau蛋白构象JDP可以在体内改变tau病理学吗？在本建议中，我们的目标是定义如何 JDP亚组识别与细胞中不同tau病理学相关的tau的不同构象， in vivo.我们将首先使用生物化学和细胞方法来了解JPD如何识别不同的 tau的构象。我们还将确定与DnaJC 7和DnaJB 6复合的tau的结构。最后， 我们将测试DnaJC 7和DnaJB 6对体内tau病理学发展的活性。我们的长期目标 是开发出能减少淀粉样蛋白沉积和减缓神经退化的疗法。这个项目正在 与NIA的使命保持一致，以支持有关衰老的生物学和临床研究。

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.