Deciphering the complexity of intracellular Tau aggregates

Tau is an intrinsically disordered protein with the key function to stabilise axonal microtubules. In several neurological disorders collectively known as Tauopathies, tau proteins form aggregates that accumulate in cells and cause neuronal damage. The molecular mechanism which leads to tau aggregation is complex and liquid–liquid phase separation (LLPS), a process that is used by cells to assemble membrane‐less organelles, has been found to be involved in Tau aggregation. De-mixing of Tau can be triggered through the addition of macromolecular crowding agents, or through coacervation (i.e. co-condensation of the positively charged Tau microtubule‐assembly domain with polyanionic RNA into liquid‐like droplets). In the complex ecosystem of the neuronal cytoplasm, it is possible that Tau undergoes crowding and coacervation at the same time. To investigate this scenario, researchers around Susanne Wegmann at DZNE in Berlin, Germany conducted a study investigating the effect of molecular crowding and RNA interaction on Tau aggregation in cells. These findings from Hochmair et al. were published in the EMBO Journal. Using an in vitro model, they find that molecular crowding is necessary to enable Tau and phosphorylated Tau coacervation with RNA. When the researchers treated HEK sensor cells with Tau:RNA condensates, they observed three categories of intracellular aggregates: CYT-Tau: large, bright cytoplasmic inclusions, NUC-Tau: often bright and nuclear, and NE-Tau: dimmer inclusions that reside at the nuclear envelope and form a thin non-uniform layer of small granule like structures. The researchers used FRAP (Fluorescence Recovery After Photobleaching) and FLIM (Fluorescence lifetime imaging) to investigate differences between the intracellular aggregate and found that NUC-Tau is the most dense followed by CYT-Tau and NE-Tau. Interestingly, Amytracker 680 labels CYT-Tau and NUC-Tau, but not NE-Tau confirming that these three types of aggregates have different morphology and molecular content. When they used Alzheimer’s Disease brain lysate instead of in-vitro prepared Tau:RNA condensate to treat HEK cells, the researchers were able to recapitulate these findings. Taken together, the study by Hochmair et al. contributes to deciphering the complexity of Tau aggregation and explains the variety of disease‐related cellular Tau accumulations.

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