Molecular and Cellular Determinants of Tau Protein Condensation into Dense Liquid Phases

The neuronal tau protein is involved in the regulation of the axonal microtubule skeleton in the brain. In neurodegenerative diseases such as Alzheimer’s disease (AD) and Frontotemporal dementia (FTD), tau becomes aberrantly phsophorylated, and aggregated tau accumulates in the neuronal soma. Phopshorylation is also involved in regulating tau’s binding to microtubules and other physiological functions. We and others recently found that tau can condensate into liquid phases and that this process is regulated by posttranslational modifications of tau: for example phosphorylation triggers, and acetylation inhibits tau LLPS. Furthermore, tau condensates can transition into aggregates with biological seeding potential, a process that could contribute to tau aggregation in the brain in the context of AD and tauopathies. In the framework of the SPP2191, we extend our previous findings and determine, which physiological and pathological conditions favor tau condensation and the transition into aggregation, both on the physicochemical and structural level in vitro as well as in the neuronal context using neuronal cultures and postmortem human brain tissue.

Current State of Research

Emerging data suggest that different kind of Tau condensates can exist and play a role in cells. In last year, we defined the physicochemical and structural differences and similarities of Tau protein condensates and coacervates in vitro, in order to understand their multiple faces in cell biology. Time-resolved DLS and SAXS experiments are in place to determine structural changes that occur in tau condensates over time. Currently, we are investigating i) the influence of PTMs important for Tau (patho)biology , such as phophorylation, on condensation of Tau both in vitro and in cells, and ii) determine the molecular composition and arrangement in Tau condensates in different contexts relevant for Tau biology and pathology.