Liquid-liquid phase separation induces pathogenic tau conformations in vitro

• DOI: 10.1038/s41467-020-16580-3
• Publication Date: 2020-06-04T10:03:02Z
• Authors: Nicholas M. Kanaan; Chelsey Hamel; Tessa Grabinski; Benjamin Combs
• Keywords: Separation (statistics)

Formation of membrane-less organelles via liquid-liquid phase separation is one way cells meet the biological requirement for spatiotemporal regulation cellular components and reactions. Recently, tau, a protein known its involvement in Alzheimer's disease other tauopathies, was found to undergo making it several proteins associated with neurodegenerative diseases do so. Here, we demonstrate that tau forms dynamic liquid droplets vitro at physiological levels upon molecular crowding buffers resemble conditions. Tau droplet formation significantly enhanced by disease-associated modifications, including AT8 phospho-epitope P301L mutation linked an inherited tauopathy. Moreover, dynamics are reduced these modified tau. Extended promoted time-dependent adoption toxic conformations oligomerization, but not filamentous aggregation. showed greatest oligomer following extended separation. These findings suggest may facilitate non-filamentous pathogenic conformations.