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Phase Transition-Mediated Tau Function and Dysfunction

相变介导的 Tau 功能和功能障碍

基本信息

批准号：
10465040
负责人：
Allan Chris Ferreon
金额：
$ 40万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10465040
关键词：
Acetylation Affect Aging Alzheimer&apos s Disease Amyloid Fibrils Behavior Brain Diseases Cell Nucleolus Cells Coupled Disease Evolution Exhibits Filament Fluorescence Spectroscopy Functional disorder Gel Heparin Heterogeneity Imaging Techniques Laboratories Lead Link Liquid substance Maps Mediating Microscopy Microtubules Minor Molecular Molecular Conformation Morphology Neurodegenerative Disorders Neurons Partner in relationship Pathologic Pathology Phase Phase Transition Phosphorylation Physiology Population Post-Translational Protein Processing Proteins Research Research Personnel Role Sodium Chloride Solid Spectrum Analysis System Tauopathies Techniques Temperature Time Tubulin Variant alpha synuclein biophysical techniques conformational conversion driving force experience experimental study fluorescence imaging hyperphosphorylated tau insight interest loss of function monomer novel therapeutic intervention protein TDP-43 protein aggregation recruit single molecule solid state stress granule tau Proteins tau aggregation tau conformation tau dysfunction tau function tau interaction tau phosphorylation

项目摘要

Project Summary Phase Transition-Mediated Tau Function and Dysfunction The proposed research will decipher the molecular mechanism of liquid-liquid phase separation (LLPS)-mediated Tau function and dysfunction. Phase-separated Tau droplets enrich tubulin and facilitate microtubule assembly (Tau function), whereas persistent droplets lead to protein aggregation. Utilizing prior extensive experience with disordered protein systems, the investigators will determine how LLPS links Tau loss-of-function and gain-of-toxic dysfunction in three stages: They will characterize how pathologic post-translational modifications (PTMs; hyperphosphorylation and hyperacetylation) modulate Tau LLPS-mediated microtubule assembly and protein aggregation (Aim 1); they will track Tau conformations that are key to both LLPS-mediated Tau function and dysfunction (Aim 2); and, they will determine how co- aggregating proteins initiate/ facilitate/ synergize Tau aggregation (Aim 3). The first Aim will utilize ensemble spectroscopy and time-lapse microscopy techniques to understand the role of PTMs in LLPS-mediated function and dysfunction. Phase transition maps of different Tau variants will be generated to characterize how different PTMs alter Tau LLPS. Effects of Tau variant co-partitioning in droplets or fibrillar aggregates on Tau function and dysfunction will also be studied. The second Aim will utilize ultrasensitive fluorescence spectroscopy techniques to track conformational conversions as monomeric Tau forms condensed droplets and as liquid droplets transform to solid states, i.e., functional (in microtubule assembled filaments) and/or dysfunctional states (amyloid fibril states). The third Aim will determine the role of co-aggregating proteins in Tau LLPS and subsequent protein aggregation. Synergistic interaction between co-phase separating proteins will be characterized. Mechanism of aggregate cross-seeding will provide insights into protein co-misfolding.

项目总结