Glaucoma is an eye disease that is so subtle and yet so damaging that it has been nicknamed the “sneak thief of sight” for its ability to progress gradually but steadily, and is often not be recognized until the disease’s advanced stages. A disease of the optic nerve involving the loss of retinal ganglion cells, about four million Americans are estimated to have it, though only half may be aware of it. While only 120,000 of those people have become blind due to the disease, it still accounts for about 10% of all cases of blindness in the United States.

Despite its high prevalence, there are still huge gaps in scientists’ understanding of the disease: what exactly causes it, what are the risk factors, and what can be done to prevent it?

Understanding Glaucoma

Andrei Surguchov, PhD, is head of the laboratory of retinal biology at the Kansas University Medical Center and Kansas City VA Medical Center. He has spent years investigating the physiological processes that cause glaucoma. “Glaucoma is a neurodegenerative disease of the optic nerve that involves the loss of retinal ganglion cells and their axons. Axons are a kind of transmitters connecting the eye with the brain. Axons form the optic nerve, which acts like an electric cable that contains about a million wires. This optic nerve is responsible for carrying images from the eye to the brain.”

The loss of retinal ganglion cells results in the eventual diminishing of sight. Patients will notice gradual loss of peripheral vision. Sometimes they develop tunnel vision, or possibly eye pain and blurred vision.

There are several known risk factors for glaucoma, the most pronounced of which are intraocular pressure and genetics. “Intraocular pressure is a significant risk factor for developing glaucoma. IOP is a function of liquid in the anterior body of the eye,” Dr. Surguchov said.

If that liquid cannot drain out of the eye through the trabecular meshwork—an area of tissue around the base of the cornea—then the pressure in the eye goes up. This is what ophthalmologists traditionally check for during routine eye appointments. However, there are many glaucoma patients that have normal IOP, and so researchers must turn to genetics. Several genes have been linked to glaucoma, but they seem to play only a small part in determining a patient’s risk for the disease.

“Only about 5% of patients have mutations in these genes,” Dr. Surguchov explained. “For about half of glaucoma patients who do not have elevated IOP or genetic predictability, the mechanisms and the triggers that lead to this pathology are not very clear and not very well understood. Unfortunately, there’s no universal or good medicine to treat glaucoma patients. That’s why we need to uncover new mechanisms. We need to identify new participating genes or proteins that may uncover the mechanisms of glaucoma.”

For the last several years, Dr. Surguchov has been engaged in a promising line of study involving one particular protein that might play a large role in developing glaucoma. “We began the search for new genes several years ago [and have since] uncovered several new genes that were unknown at that time in the retina. One of them attracted my attention. We called it gamma-synuclein,” Dr. Surguchov said.

He was attracted to the protein because it belonged to a family of proteins implicated in Parkinson’s disease. “Since the retina is considered a part of the brain, I decided that we probably needed to go ahead with this new gene and study it in more detail, because the mechanisms of neurodegeneration in the brain and in the retina may be similar,” Dr. Surguchov explained.

The Role of Retinal Ganglion Cells

Dr. Surguchov soon discovered that not only is gamma-synuclein present in the retina, but it is a marker for retinal ganglion cells. “If we stain the retina with antibodies specific for gamma synuclein, we found the staining only in the retinal ganglion cells,” he said.

Retinal ganglion cells consist of several different subtypes of cells that vary widely anatomically and serve different functions. Those include a subtype of retinal ganglion cell that is intrinsically photosensitive, making it very similar to photoreceptor cells. “It was just a recent discovery that we don’t know enough about these type of cells,” Dr. Surguchov said.

Dr. Surguchov believes that a study of the loss of retinal ganglion cells due to glaucoma is important in understanding the disease, and that gamma-synuclein can play a large role. “Signals are transmitted to the brain through retinal ganglion cells and their axons, and gamma-synuclein is a marker of these cells,” he explained. “And we need to identify what subtypes of retinal ganglion cells can be identified by this marker, and we’re working on this now. We don’t know yet whether photosensitive retinal ganglion cells contain this marker or not. Hopefully we will know that soon.”

The important thing is that now researchers have a marker for the types of cells that die in glaucoma, allowing them to better see and track the progress of the disease.

Possible Protein Build-Up

But does gamma-synuclein play a role in causing glaucoma? Its close cousin alpha-synuclein has been strongly implicated in Parkinson’s disease. Alpha-synuclein, which is normally an unstructured protein, can aggregate in nerve cells leading to PD. “We need to understand whether the same may happen with gamma-synuclein and retinal ganglion cells,” Dr. Surguchov said.

If gamma-synuclein aggregates in the same way as alpha-synuclein, perhaps that accumulation in retinal ganglion cells can lead to their death, and thus lead to glaucoma. “The important point is that synucleins are different from the majority of globular proteins. They do not acquire folded structure. Instead, they are so-called naturally unfolded proteins. As a result, they tend to aggregate to form pathological conditions,” Dr. Surguchov explained. “Now we are studying factors that stimulate synuclein aggregation and studying how these aggregations are formed and what is the nature of these links that connect individual molecules in these aggregates.”

Dr. Surguchov is currently studying whether such an aggregation occurs, as well as how production of synclines is regulated in the body. “We found that there is an optimal concentration of gamma-synuclein in cells. And when we artifi cially signifi cantly increase or reduce these optimal levels, the consequences are detrimental for the cells,” he said.

Should it be found that an accumulation of gamma-synuclein in the cells leads to their death, understanding how to control production of the protein might be key in terms of glaucoma treatment. “It would be important to find any substances that would prevent these toxic aggregates and prevent cell death,” Dr. Surguchov declared.