Molecular Mechanism of Ganglion Cell Death in Glaucoma

Glaucoma is an eye disease that is often associated with an increase in intraocular pressure. All of the current treatments of glaucoma are directed at reducing this pressure in the hopes that it will prevent the progressive loss of sight that is characteristic of this disease. But glaucoma is much more than a problem of increased eye pressure. Blindness from this affliction is caused by the death of a certain cell type in the retina, the ganglion cells. Scientists know very little about either what causes this cell death or how these cells die. If we understand more about these two important aspects of glaucoma, then perhaps we would be able to devise new and additional treatments to prevent this cell loss.

We have been studying the question of how cells die in glaucoma. We now know that they die by a process called apoptosis. This form of cell death is somewhat unique because it is entirely controlled by genes expressed in the dying cell. Apoptosis is a very natural process that is utilized by many cells in the body during normal tissue homeostasis-that is, when cells grow too old, they are removed from the body and replaced with new ones. The only time ganglion cells normally undergo apoptosis is during embryonic development, when the retina is being shaped and organized into a functional organ. We think in glaucoma, adult ganglion cells accidentally receive the same signal to execute the apoptosis program that they normally receive during development.

Once activated in cells, the apoptotic program is controlled by a variety of genes. A primary point of control, however, may center around the interaction of two genes called bcl-x and bax. The products of these two genes can bind to each other and form a molecular switch. High levels of the bcl-x gene product in a cell promotes its survival, while high levels of the bax gene product promotes cell death. Our previous studies showed that retinal ganglion cells express the bcl-x gene. During early stages of apoptosis in these cells, the level of bcl-x drops significantly, possibly as a mechanism to create an increase in the relative amount of the bax protein and activate cell death. We have hypothesized that if we can artificially increase bcl-x expression in ganglion cells, we may be able to block their death in glaucoma. To test this hypothesis, we propose to create a synthetic gene for bcl-x and insert it into laboratory mice. Mice with this gene will be able to express bcl-x specifically in their ganglion cells. Unlike mice without this synthetic gene, however, these “transgenic” mice will be able to continue to express bcl-x even after the ganglion cells receive a stimulus to start apoptosis. Using various techniques to measure ganglion cell death, we will be able to determine if artificially high bcl-x expression will keep ganglion cells alive in experimental situations very similar to glaucoma.

How will these experiments have an impact on future treatments of glaucoma? At one level, these studies will shed light onto the key genes that control ganglion cell death. A better understanding of this process may lead us to develop new and more effective treatments aimed at blocking parts of the apoptotic pathway. Our future direction in this research is to develop ways that we can introduce bcl-x genes into ganglion cells in animals with glaucoma. This strategy may someday allow us to use gene therapy to treat this debilitating eye disease.