Roles of Palmitoylation in Progression of Glaucoma
Glaucoma is a disease that causes blindness because the connections between the eye and brain are damaged. This damage is caused by activation of ‘executioner’ proteins that cause the connections to degenerate, and loss of ‘survival’ proteins that normally protect the connections. We have evidence that important executioner and survival proteins are modified with a sticky, fatty tag. We will determine the importance of this ‘tagging’ process for the damage seen in glaucoma, which may reveal new ways to treat this disease.
This project will study how the addition of a sticky, fatty tag called palmitate controls the function of enzymes with key roles in glaucoma, and may reveal new ways to slow glaucoma progression by regulating this tagging process.
In a first set of experiments, we will replace the normal forms of specific ‘executioner’ enzymes in retinal cells with mutant forms that cannot be tagged with palmitate. We will then determine whether blocking the palmitate tagging can protect cells in an experimental model of glaucoma. We will also examine how preventing the palmitate tag affects the activity of the executioner enzymes at the molecular level.
Interestingly, an unstable protein that is essential for the integrity of the optic nerve is also modified with the palmitate tag. We think we have identified the enzyme that adds palmitate to this ‘survival’ protein. In a second set of experiments we will determine whether mice that lack this enzyme spontaneously develop symptoms of glaucoma. If so, we will see whether delivering a stabilized version of the survival protein can slow the glaucoma progression.
Although the executioner enzymes and survival proteins have been identified by other researchers (including those who benefitted from BrightFocus support), how palmitate addition regulates these proteins in the eye has never been addressed. In addition to this conceptual novelty, the techniques that we will use to replace the normal forms of proteins with mutant forms are also cutting edge.
Once this work is complete we should have a much clearer picture of the importance of the palmitate lipid for both survival and degeneration of retinal cells in glaucoma. Importantly, because specific enzymes add and remove the palmitate tag from ‘executioner’ and ’survival’ proteins, our work should also reveal whether these enzymes could be therapeutically targeted to increase retinal survival and/or prevent degeneration.