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.
About the Researcher
I first became fascinated by biology during my undergraduate studies at the University of Cambridge. I became particularly interested in intracellular signaling and therefore joined the laboratory of Sir Philip Cohen at the University of Dundee to pursue a PhD in this area. During this time I became especially interested in cell signaling in the nervous system and therefore carried out postdoctoral research in the laboratory of Dr. Rick Huganir at John Hopkins University. Much of my postdoctoral research focused on physiological signaling in healthy neurons, but in my own laboratory I became very interested in how different signaling pathways might control the balance between degeneration and survival in pathological conditions. Most recently I have become particularly interested in roles of such pathways in progression of glaucoma and my lab expended considerable time and effort to develop experimental models of this disease. I am truly grateful to the BrightFocus Foundation and its donors for supporting our research and providing a means for my laboratory to begin to address key questions in this new and exciting area.
Virtually all of us have seen those we care about suffering from the devastating effects of neurodegenerative disease. With few effective treatments currently available, such conditions are hard for sufferers and their loved ones to bear. However, exciting recent progress in the case of one of these conditions, glaucoma, has markedly increased our understanding of key players in the disease process, raising the possibility that new therapeutic strategies may be within reach. Equally exciting is the possibility that glaucoma therapies that target conserved neuronal death or survival pathways might be transferable to treat other neurodegenerative conditions. My research seeks to gain more understanding of the glaucoma disease process and hence determine whether these tantalizing possibilities could become a reality. The generosity of the BrightFocus Foundation and its donors makes pursuing ‘high risk, high reward’ strategies of this type possible and we greatly appreciate their support.
First published on: July 3, 2019
Last modified on: July 3, 2019