Abstract
Tau is a microtubule-associated protein that plays a major role in Alzheimer's disease (AD) and other tauopathies. Recent reports indicate that, in the presence of crowding agents, tau can undergo liquid-liquid phase separation (LLPS), forming highly dynamic liquid droplets. Here, using recombinantly expressed proteins, turbidimetry, fluorescence microscopy imaging, and fluorescence recovery after photobleaching (FRAP) assays, we show that the divalent transition metal zinc strongly promotes this process, shifting the equilibrium phase boundary to lower protein or crowding agent concentrations. We observed no tau LLPS-promoting effect for any other divalent transition metal ions tested, including Mn2+, Fe2+, Co2+, Ni2+, and Cu2+ We also demonstrate that multiple zinc-binding sites on tau are involved in the LLPS-promoting effect and provide insights into the mechanism of this process. Zinc concentration is highly elevated in AD brains, and this metal ion is believed to be an important player in the pathogenesis of this disease. Thus, the present findings bring a new dimension to understanding the relationship between zinc homeostasis and the pathogenic process in AD and related neurodegenerative disorders.
Highlights
Tau is a microtubule-associated protein that plays a major role in Alzheimer’s disease (AD) and other tauopathies
This can occur upon the addition of RNA [13] or, for protein alone, in the presence of crowding agents that mimic high concentration of macromolecules in the intracellular environment (14 –16)
Even though it was originally suggested that only phosphorylated tau can undergo LLPS in the absence of polyanions such as RNA [14], more recent studies revealed that this process does not require phosphorylation and that tau LLPS is driven by attractive electrostatic intermolecular interactions between oppositely charged domains of the protein [15]
Summary
Tau is a microtubule-associated protein that plays a major role in Alzheimer’s disease (AD) and other tauopathies. In the presence of crowding agents, tau can undergo liquid–liquid phase separation (LLPS), forming highly dynamic liquid droplets. Because the environment inside phase-separated droplets is distinct from that of the surrounding aqueous phase, LLPS may have a major effect on the formation of pathological protein aggregates in AD and other neurodegenerative disorders [17,18,19,20]. We demonstrate that zinc ions can strongly promote LLPS of tau and provide insight into the mechanism of this process. These findings are of potential importance for understanding the pathogenic process in AD.
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