Chaperone-Mediated Regulation of Tau Phase Separation, Fibrillation, and Toxicity

Biological condensates are involved in several essential processes but may also be tangled into disease progression in protein misfolding diseases such as Alzheimer's disease and tauopathies. One hallmark of these disorders is the appearance of fibrillar aggregates formed by microtubule-stabilizing Tau protein. Notably, Tau can also assemble into biological condensates and droplets via liquid-liquid phase separation (LLPS). The molecular mechanisms of the conversion of functional Tau toward insoluble fibrils, potentially via LLPS processes, remain largely unknown, and efficient treatment approaches to target toxic pathways and species are still missing. Here, we show that the molecular chaperone-like Bri2 BRICHOS domain efficiently inhibits full-length Tau fibril formation and subsequent neurotoxicity by specifically suppressing secondary nucleation processes. Further, at substoichiometric ratios, Bri2 BRICHOS modulates the potency of Tau to form droplets, incorporates into Tau droplets, and alters the dynamic behavior of Tau. In contrast, at superstoichiometric Bri2 BRICHOS ratios, Tau droplet formation is abolished. Finally, Bri2 BRICHOS reduces Tau fibril toxicity in electrophysiological experiments on hippocampal slice preparations. Taken together, Bri2 BRICHOS targets molecular processes related to protein misfolding, where our study provides molecular insights into how the inhibition of secondary nucleation pathways and modulated droplet formation are eventually linked to attenuated neurotoxicity.