Biomolecular Tau condensation is linked to Tau accumulation at the nuclear envelope

Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and produce condensates with a strong affinity to charged surfaces. During condensate-mediated microtubule polymerization, this synergy enhances bundling and spatially arranges microtubules. We further show that different Tau condensates efficiently induce pathological Tau in cells, including small accumulations at the nuclear envelope that correlate with nucleocytoplasmic transport deficits. Fluorescent lifetime imaging reveals different molecular packing densities of Tau in cellular accumulations, and a condensate-like density for nuclear envelope Tau. These findings suggest that a complex interplay between interaction partners, post-translational modifications, and molecular crowding regulates the formation and function of Tau condensates. Conditions leading to prolonged existence of Tau condensates may induce the formation of seeding-competent Tau and lead to distinct cellular Tau accumulations. ### Competing Interest Statement The authors have declared no competing interest. * AD : Alzheimer’s disease CFP : cyan fluorescent protein DLS : dynamic light scattering FTD : frontotemporal dementia LLPS : liquid-liquid phase separation MTs : microtubules R : radius of hydration (Stokes radius) YFP : yellow fluorescent protein FRAP : fluorescence recovery after photobleaching FLIM : fluorescence lifetime imaging microscopy FRET-FLIM : Foerster Resonance energy transfer measured by FLIM of the donor CYT : cytosolic Tau inclusions NUC : intranuclear Tau accumulations NE : Tau accumulations at the nuclear envelope hepAGG : Tau aggregated in the presence of heparin at a 4:1 (Tau:heparin) ratio mesoscopic clusters : R ∼100-200 nm microscopic condensates : R ∼1000 nm monomeric/clusters/condensates : refers to degree of Tau assembling Tau coacervation : LLPS driven by interaction of Tau with polyanions in the presence of PEG Tau condensation : term for all LLPS processes