TogoPhosTAC delivers a phosphatase, an enzyme that removes phosphate tags from proteins, to a selected target
TogoPhosTAC delivers a phosphatase, an enzyme that removes phosphate tags from proteins, to a selected target
TogoPhosTAC combines a lipid particle that delivers either a phosphatase or mRNA, which provides the instructions for making the enzyme, with a small targeting molecule. This molecule brings the enzyme into contact with the intended protein. The authors report that, in male PS19 transgenic mice, a model of tauopathy, the system reduced pathological phosphorylation of tau, the accumulation of pathological tau in several brain regions, and behavioral impairments associated with Alzheimer's disease.
On August 14, Nature Communications published an article on TogoPhosTAC. Phosphate tags alter how proteins function, including their activity, their interactions with other proteins, and, in some cases, their tendency to form aggregates. Kinases add these tags, while phosphatases remove them. The authors sought a way to direct phosphate removal toward one selected protein.
PhosTAC is a molecule with two binding sites. One binds to an artificial tag on a phosphatase, while the other recognizes the target protein. Bringing the two together allows the phosphatase to remove a phosphate tag from the target. In earlier experiments, the cell produced the required engineered phosphatase itself. In TogoPhosTAC, a ready-made phosphatase or mRNA, which instructs the cell to produce the phosphatase temporarily, is packaged together with the targeting molecule in a lipid particle and delivered into the cell.
The full early manuscript describes cellular tests of this design. The authors first confirmed that the delivered phosphatase was active and then directed it toward EGFR, a receptor that transmits growth signals to the cell. Compared with the same phosphatase lacking the artificial tag, the version used with the targeting molecule produced a greater reduction in phosphorylation at a specific EGFR site, Y1068. In a cellular tau model, the targeting molecule linked tau to the delivered PP2A component. The catalytic component of the enzyme, which removes phosphate tags, then joined this complex. In a control measurement, the phosphate tag on AKT, a standard PP2A target, remained intact, indicating that the targeting molecule directed the phosphatase toward tau.
In the published article, the authors tested the system in male PS19 transgenic mice. TogoPhosTAC was administered into the hippocampus or through the nose. The authors report reductions in pathological tau phosphorylation at five positions, the accumulation of pathological tau in several brain regions, and behavioral impairments associated with Alzheimer's disease.