Tau aggregation that forms neurofibrillary tangles is a hallmark of tauopathies and in particular, Alzheimer’s disease. Several studies have shown that liquid-liquid phase separation (LLPS) condensation of Tau through mechanisms such as macromolecular crowding or coacervation has been shown to promote liquid-like condensates of Tau promoting an aggregated state. Recently, Hochmair et al. investigated the mechanism by which molecular crowding and RNA synergize to promote Tau condensates in vitro and in cell-based studies. Preliminary experiments utilized in vitro models to look at Tau condensation in the presence of PEG, a molecular crowding agent, and polyanionic RNA molecules; interestingly, the Tau-LLPS condensates had both the Tau and RNA contained in the droplets while PEG was excluded. Time-resolved dynamic light scattering experiments were performed to track the growth of these particles over time, which identified droplet coalescence as a contributing factor for particle growth only when both RNA and PEG were present. Additional studies were conducted to show that molecular crowding was necessary for both Tau and phosphorylated Tau condensation at physiological ion concentrations. The group next looked at how the condensation of Tau affected its interaction with Tubulin and showed that tubulin and RNA appeared to compete for co-condensation with Tau. However, the Tau-PEG-RNA condensate appeared to promote thick microtubule bundles with defined interaction between Tau, RNA, and microtubules. These condensates were also examined in cells and were shown to promote pathological Tau aggregates that had localized preferences near the nuclear envelope. Collectively, these studies highlight the importance of understanding the interplay between molecular crowding, interacting molecules, and other factors that contribute to Tau aggregation. Cytoskeleton Inc’s Tubulin Protein (Fluorescent HiLyte 647) (Cat. #TL670M) was essential for the in vitro studies investigating the interplay between Tau, RNA, and tubulin.
Above: Schematic showing Tau condensation in different environments
Link to Citation:
Hochmair J. et al. Molecular crowding and RNA synergize to promote phase separation, microtubule interaction, and seeding of Tau condensates. EMBO J. 2022 Jun 1;41(11):e108882. doi: 10.15252/embj.2021108882. Epub 2022 Mar 17.
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