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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：
10710398
负责人：
Galia Debelouchina
金额：
$ 18.48万
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/10710398
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 Cytoplasm DNA DNA Binding DNA Damage DNA Sequence Development Disease Environment Experimental Designs Fluorescence Microscopy Fluorescence Recovery After Photobleaching Gel Gene Expression Gene Expression Regulation Gene Silencing Heterochromatin Histones Image In Vitro Knock-out Liquid substance Literature Magic Methylation 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 biophysical properties diagnostic strategy epigenetic marker experimental study gene repression in vivo live cell imaging mimetics novel diagnostics novel therapeutics reconstitution solid state nuclear magnetic resonance tau Proteins tau aggregation tau expression tau function tau interaction tau-1 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.

项目总结