Zinc enhances liquid-liquid phase separation of Tau protein and aggravates mitochondrial damages in cells

Intraneuronal neurofibrillary tangles composed of Tau aggregates have been widely accepted as an important pathological hallmark of Alzheimer's disease. Liquid-liquid phase separation (LLPS) of Tau can lead to its aggregation, and Tau aggregation can then be enhanced by zinc. However, it is unclear whether zinc modulates the formation of Tau stress granules in cells. We herein report that zinc promotes the formation of stress granules containing a pathological mutant delta;K280 of full-length human Tau. Furthermore, zinc promotes LLPS of & UDelta;K280 of full-length Tau, shifting the equilibrium phase boundary to a lower protein concentration, and modulates the liquid nature of droplets formed by this pathological mutation. Zinc also promotes pathological phosphorylation of & UDelta;K280 in neuronal cells, and aggravates mitochondrial damage and elevates reactive oxygen species production induced by Tau aggregation. Importantly, we show that treatment of cells with zinc increases the interaction between full-length Tau and G3BP1 inside stress granules to promote the formation of Tau filaments and increase Tau toxicity in neuronal cells. Collectively, these results demonstrate how Tau condensation and mitochondrial damages induced by Tau aggregation are enhanced by zinc to deteriorate the pathogenesis of Alzheimer's disease, bridging the gap between Tau LLPS and aggregation in neuronal cells.

Automated summary

Zinc promotes liquid-liquid phase separation and aggregation of full-length Tau, resulting in the formation of stress granules and interaction with G3BP1, leading to increased Tau filaments and neuronal toxicity. Additionally, zinc aggravates mitochondrial damage and reactive oxygen species production induced by Tau aggregation, further deteriorating the pathogenesis of Alzheimer's disease.