Phase separation of nuclear tau and its role in gene regulation

核tau蛋白的相分离及其在基因调控中的作用

基本信息

批准号：
10524696
负责人：
Galia Debelouchina
金额：
$ 22.49万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524696
关键词：
Affect Affinity Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Amyloid Amyloid Fibrils Architecture Behavior Binding Biological Assay Biophysics Cell Communication Cell Nucleus Cell physiology Cells Chromatin Chromatin Remodeling Factor Chromosomal Stability Coupled Crowding DNA DNA Binding DNA Damage DNA Sequence Development Disease Environment Fluorescence Microscopy Fluorescence Recovery After Photobleaching Gel Gene Expression Gene Expression Regulation Gene Silencing Heterochromatin Histones Image In Vitro Knock-out Lead Liquid substance Literature Magic Microtubule-Associated Proteins Microtubules Molecular Monitor Mutation NMR Spectroscopy Neurofibrillary Tangles Neurons Normal Cell Nuclear Nuclear Proteins Nucleic Acids Phase Phosphorylation Play Post-Translational Protein Processing Process Proteins Published Comment Regulation Relaxation Research Ribosomal DNA Role Satellite DNA Stress Testing Untranslated RNA Up-Regulation base biophysical properties design diagnostic strategy epigenetic marker experimental study gene repression in vivo live cell imaging novel diagnostics novel therapeutics reconstitution solid state tau Proteins tau expression tau function tau interaction tau phosphorylation transcriptome sequencing

项目摘要

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.

项目摘要 Tau是一种在阿尔茨海默氏病的神经原纤维缠结中发现的微管相关蛋白患者。 tau可以在体外和体内形成淀粉样蛋白原纤维，并且可以在拥挤的药物和核酸的存在。虽然大部分研究都集中在其微管上在阿尔茨海默氏病的背景下，相关的功能和异常聚集，tau也发现核。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形成，尽管这些功能背后的分子机制具有在很大程度上仍然是神秘的。 Tau在异染色质中的存在特别有趣，因为它本地化为可以预测将其分离的环境与其他已知蛋白质这样做的环境。因此，在这个探索性建议，我们旨在检验一个假设，即tau可能在异染色质调节中发挥作用通过相分离机制。我们还假设异常的磷酸化和疾病 - 相关突变可能会破坏这一过程，并可能导致细胞调节基因的能力受损表达。我们建议通过体外生物物理和结构测定测试这些假设，并耦合基于细胞的实验旨在更好地了解潜在功能和生物物理核tau的性质。我们旨在提供有关背后分子机制的新观点阿尔茨海默氏病与淀粉样假说不同，并希望告知新的治疗和诊断方法。