Tubulin transforms Tau and -synuclein condensates from pathological to physiological

Proteins phase-separate to form condensates that partition and concentrate biomolecules into membraneless compartments. These condensates can exhibit dichotomous behaviors in biology by supporting cellular physiology or instigating pathological protein aggregation1-3. Tau and - synuclein (Syn) are neuronal proteins that form heterotypic (Tau:Syn) condensates associated with both physiological and pathological processes. Tau and Syn functionally regulate microtubules8-12, but are also known to misfold and co-deposit in aggregates linked to various neurodegenerative diseases4,5,6,7, which highlights the paradoxically ambivalent effect of Tau:Syn condensation in health and disease. Here, we show that tubulin modulates Tau:Syn condensates by promoting microtubule interactions, competitively inhibiting the formation of homotypic and heterotypic pathological oligomers. In the absence of tubulin, Tau-driven protein condensation accelerates the formation of toxic Tau:Syn heterodimers and amyloid fibrils. However, tubulin partitioning into Tau:Syn condensates modulates protein interactions, promotes microtubule polymerization, and prevents Tau and Syn oligomerization and aggregation. We distinguished distinct Tau and Syn structural states adopted in tubulin-absent (pathological) and tubulin-rich (physiological) condensates, correlating compact conformations with aggregation and extended conformations with function. Furthermore, using various neuronal cell models, we showed that loss of stable microtubules, which occurs in Alzheimers disease and Parkinsons disease patients13,14, results in pathological oligomer formation and loss of neurites, and that functional condensation using an inducible optogenetic Tau construct resulted in microtubule stablization. Our results identify that tubulin is a critical modulator in switching Tau:Syn pathological condensates to physiological, mechanistically relating the loss of stable microtubules with disease progression. Tubulin restoration strategies and Tau-mediated microtubule stabilization can be potential therapies targeting both Tau-specific and Tau/Syn mixed pathologies.