In a study published in the Journal of the American Chemical Society, scientists explore how a brain protein called tau changes its behavior when a small chemical group called a phosphate attaches to it—a process known as phosphorylation.
Under normal conditions, tau helps maintain healthy brain cells, but when it starts clumping together, it is linked to neurodegenerative diseases such as Alzheimer's disease.
The research team compared two forms of tau: one with phosphate groups attached (called phosphorylated tau, or p-tau) and one without. Uniquely, they engineered bacteria to produce p-tau using a specialized design called PIMAX.
They found that only p-tau, not regular tau, could spontaneously form tiny droplets—micrometers in size—through a process known as liquid–liquid phase separation (LLPS), which is similar to how oil separates from water.
This droplet formation happened naturally as the temperature shifted from cold (4°C) to room temperature and was driven by electrostatic and hydrophobic interactions. Remarkably, the droplets disappeared upon cooling, showing that the process is reversible.
Further experiments revealed that attaching just a few phosphate groups—between two and nine—was enough to make tau more flexible and loosely folded, allowing it to form droplets.
The team also discovered that RNA can induce droplet formation in both tau and p-tau, but unlike p-tau's reversible self-coacervation, the RNA-driven process is irreversible and occurs on a different timeline.
Interestingly, the LLPS-forming ability does not lead to amyloid fibril formation. Neither tau nor p-tau form amyloid fibrils on their own; trigger agents such as dextran sulfate or RNA were required.
Surprisingly, dextran sulfated-induced tau/p-tau fibrils, RNA-induced tau/p-tau fibrils, and tau/p-tau under LLPS conditions each led to tau fragment aggregation in distinct cellular locations of the biosensor cells.
Most notably, only p-tau under LLPS conditions induced aggregation around the cell nucleus—a pattern that closely resembles what is observed in the brains of Alzheimer's patients. This novel observation may provide important clues into how the disease originates.
"This is a significant discovery," said Prof. Rita P.–Y. Chen. "Our results demonstrate how a simple chemical modification—phosphorylation—can fundamentally alter tau's behavior in cells, offering new insights into the early events of Alzheimer's disease."
"Currently, there is no reliable mouse model that fully mimics the human condition. We are now working on developing a new mouse model that more closely reflects the pathological features seen in Alzheimer's patients," she said.
More information: Mohammadreza Allahyartorkaman et al, Phosphorylation-Induced Self-Coacervation versus RNA-Assisted Complex Coacervation of Tau Proteins, Journal of the American Chemical Society (2025). DOI: 10.1021/jacs.4c14728
Journal information: Journal of the American Chemical Society
Provided by National Taiwan University