Phase separation of nuclear tau and its role in gene regulation

项目摘要 Tau是一种微管相关蛋白，存在于阿尔茨海默病患者大脑中的神经元缠结中 患者Tau可以在体外和体内形成淀粉样蛋白原纤维，并且可以在体内经历液-液相分离。 拥挤剂和核酸的存在。虽然大部分tau蛋白的研究都集中在微管上， 在阿尔茨海默病的背景下，tau蛋白也存在于阿尔茨海默病的相关功能和异常聚集中。 原子核越来越多的证据表明，细胞核tau蛋白可能在DNA保护、染色体修复和细胞凋亡中发挥作用。 稳定性和异染色质形成，尽管这些功能背后的分子机制 很大程度上仍然是个谜。 Tau蛋白在异染色质中的存在特别有趣，因为它定位于一个细胞核， 它将被预测为相分离的环境，已知其他蛋白质也会这样做。因此在 这个探索性的提议， 我们的目标是验证一个假设，即tau蛋白可能在异染色质调节中发挥作用， 通过相分离机制。我们还假设异常磷酸化和疾病- 相关的突变可能会破坏这一过程，并可能导致细胞调节基因表达的能力受损。 表情我们建议通过体外生物物理和结构测定来测试这些假设， 以细胞为基础的实验，旨在更好地了解潜在的功能和生物物理 核tau的性质。我们的目标是提供一个新的观点，关于背后的分子机制， 阿尔茨海默氏病与淀粉样蛋白假说不同，希望能为新的 治疗和诊断方法。

Project summary Tau is a microtubule-associated protein found in neurofibrillary tangles in the brains of Alzheimer’s disease patients. Tau can form amyloid fibrils both in vitro and in vivo and can undergo liquid-liquid phase separation in the presence of crowding agents and nucleic acids. While much of tau research has focused on its microtubule associated functions and aberrant aggregation in the context of Alzheimer’s disease, tau is also found in the nucleus. Mounting evidence has suggested that nuclear tau might play a role in DNA protection, chromosome stability, and heterochromatin formation although the molecular mechanisms behind these functions have largely remained enigmatic. Tau’s presence in heterochromatin is especially intriguing, since it localizes to an environment where it would be predicted to phase separate, with other proteins known to do so. Therefore, in this exploratory proposal, we aim to test a hypothesis that tau might play a role in heterochromatin regulation through a phase separation mechanism. We also hypothesize that aberrant phosphorylation and disease- relevant mutations may disrupt this process and may lead to compromised cellular ability to regulate gene expression. We propose to test these hypotheses through in vitro biophysical and structural assays, coupled with cell-based experiments designed to gain better understanding of the potential functions and biophysical properties of nuclear tau. We aim to provide a new viewpoint regarding the molecular mechanisms behind Alzheimer’s disease that is distinct from the amyloid hypothesis and hope to inform the development of new therapeutic and diagnostic approaches.