Language
English
Publication Date
2-26-2025
Journal
Biomolecules
DOI
10.3390/biom15030336
PMID
40149872
PMCID
PMC11940599
PubMedCentral® Posted Date
2-26-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Tau is a microtubule-associated protein that undergoes liquid-liquid phase separation (LLPS) to form condensates under physiological conditions, facilitating microtubule stabilization and intracellular transport. LLPS has also been implicated in pathological Tau aggregation, which contributes to tauopathies such as Alzheimer's disease. While LLPS is known to promote Tau aggregation, the relationship between Tau's structural states and its phase separation behavior remains poorly defined. Here, we examine how oligomerization modulates Tau LLPS and uncover key distinctions between monomeric, oligomeric, and amyloidogenic Tau species. Using dynamic light scattering and fluorescence microscopy, we monitored oligomer formation over time and assessed oligomeric Tau's ability to undergo LLPS. We found that Tau monomers readily phase separate and form condensates. As oligomerization progresses, Tau's propensity to undergo LLPS diminishes, with oligomers still being able to phase separate, albeit with reduced efficiency. Interestingly, oligomeric Tau is recruited into condensates formed with 0-day-aged Tau, with this recruitment depending on the oligomer state of maturation. Early-stage, Thioflavin T (ThT)-negative oligomers co-localize with 0-day-aged Tau condensates, whereas ThT-positive oligomers resist condensate recruitment entirely. This study highlights a dynamic interplay between Tau LLPS and aggregation, providing insight into how Tau's structural and oligomeric states influence its pathological and functional roles. These findings underscore the need to further explore LLPS as a likely modulator of Tau pathogenesis and distinct pathogenic oligomers as viable therapeutic targets in tauopathies.
Keywords
tau Proteins, Humans, Protein Multimerization, Alzheimer Disease, Phase Separation, Benzothiazoles, tauopathy, LLPS, tau oligomers, neurodegeneration, tau pathology
Published Open-Access
yes
Recommended Citation
Lucas, Lathan; Tsoi, Phoebe S; Ferreon, Josephine C; et al., "Tau Oligomers Resist Phase Separation" (2025). Faculty, Staff and Students Publications. 6532.
https://digitalcommons.library.tmc.edu/baylor_docs/6532