Phase separation of nuclear tau and its role in gene regulation

项目总结 Tau是一种微管相关蛋白，存在于阿尔茨海默病患者脑内的神经原纤维缠结中 病人。Tau在体外和体内都能形成淀粉样纤维，并能在体内发生液-液相分离。 拥挤剂和核酸的存在。虽然tau的大部分研究都集中在它的微管上 相关功能和异常聚集在阿尔茨海默病的背景下，tau也在 原子核。越来越多的证据表明，核tau可能在DNA保护、染色体中发挥作用。 稳定性和异染色质的形成，尽管这些功能背后的分子机制 这在很大程度上仍然是个谜。 Tau在异染色质中的存在特别耐人寻味，因为它定位于一个 预测它会与其他已知蛋白质相分离的环境。因此，在 这个探索性的提议， 我们的目标是验证tau可能在异染色质调节中起作用的假设。 通过相分离机制。我们还假设异常的磷酸化和疾病- 相关突变可能会扰乱这一过程，并可能导致细胞调节基因的能力受损 表情。我们建议通过体外生物物理和结构分析来检验这些假说， 通过基于细胞的实验来更好地了解潜在的功能和生物物理 原子核tau的性质。我们的目标是为研究其背后的分子机制提供一个新的观点。 阿尔茨海默病不同于淀粉样蛋白假说，并希望告知新的发展 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.