Surface-induced tau condensation generates a selective microenvironment around microtubules
Year: 2026
Type: preprint
Abstract: Tau is a neuron-specific microtubule-associated protein that can self-associate into pathological insoluble aggregates or phase separate into condensates whose (patho)physiological role is debated. Recent studies suggest that intracellular surfaces can locally promote biomolecular condensation, even at low molecular concentrations. While microtubules in neurons provide an extensive tau-interaction surface, their role in tau phase separation remains unclear. Employing theory and in vitro experiments, we here demonstrate that tau forms multilayered condensates on microtubules at physiological concentrations via a prewetting-like transition. Concomitant tau–microtubule and tau–tau interactions explain the experimentally observed cooperative binding of the innermost tau layer directly adsorbed to the microtubule. The formation of this layer is dictated by the spacing of tubulin dimers within the microtubule lattice. Additional tau layers, driven by tau–tau interactions and independent of lattice spacing, are finite in thickness and unstable away from the microtubule surface. While the microtubule-adsorbed tau can selectively restrict proteins from the microtubule surface, the multilayered tau condensates can recruit tau interactors, such as RNA or soluble tubulin, highlighting the distinct roles of the condensate layers. Our results suggest that a prewetting-like transition constitutes a general physical mechanism for organizing liquid-like biomolecular layers of defined composition on charged intracellular surfaces. Graphical abstract Driven by a pre-wetting-like transition, at concentrations about two orders of magnitude below the critical concentration required for phase separation in solution (which would be required for any possible Plateau-Rayleigh instability), through cooperative binding, tau forms multilayered condensates enveloping microtubules. The condensates consist of an adsorbed layer of slow-turnover tau molecules interacting directly with the microtubule surface (protective against e.g. severing enzymes) and several layers of high-turnover condensed tau sustained by tau-tau interaction only (selectively recruiting e.g. free tubulin).
Institutions: Czech Academy of Sciences, Czech Academy of Sciences, Institute of Biotechnology, Homi Bhabha National Institute, Institute of Mathematical Sciences, Charles University, Centre National de la Recherche Scientifique, Inserm, Université Paris Sciences et Lettres, Université Paris-Saclay, Intégrité du génome, ARN et cancer, Institut Curie
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7203826753