How Does a High IOP Cause Vision Loss?

Since the 1800s it has been known that high intraocular pressure (IOP) can result in permanent loss of vision. More recently it has been discovered that Glaucoma results from a selective loss of a particular cell in the eye called the Retinal Ganglion Cell. What has not been known, however, is why an elevated IOP would result in damage or death of the Retinal Ganglion Cells (RGCs). Plenty of theories have been suggested. Extremely high eye pressures, for example, could physically damage RGCs or cut off the blood supply to the optic nerve and retina. The problem with these theories is that most people with glaucoma lose vision with eye pressure that is well below what would be necessary to cause physical tissue damage or loss of blood supply.

It’s in the Genes

The risk of developing glaucoma is higher among those with family members who have glaucoma. This has led to the search for the genes that might be associated with glaucoma. Two such genes are SIX6 and p16INKda.^[1] Genes can have intimidating names and I personally find it difficult to keep such odd letter-number combinations straight in my own head. So, I secretly rename them in playful ways that will help me remember what they do. For example, in my head SIX6 is “Agent 66” and p16INK4a is “Pinky”.

SIX6 (”Agent 66”) is involved in eye development.^[2] One variation of this gene, in particular, has a strong association with primary open angle glaucoma.^[3]

When p16INK4a (”Pinky”) is expressed a cell will stop growing.^[4] Cells, like businesses, must “grow or die”. So, when a cell stops growing it’s essentially on its way out. This is called “cellular senescence”. Expression of p16INK4a, then, is a death sentence for a cell. Indeed, removal of cells expressing p16INK4a from laboratory mouse tissue can “prevent or delay age-related deterioration”.^[5] Of particular interest is that in a rat model of glaucoma p16INK4a was significantly elevated.^[6]

It appears that when the IOP is increased SIX6 is activated within Retinal Ganglion Cells. The proteins created by the SIX6 gene interact with p16INK4a.^[7] Expression of p16INK4a then results in a cascade of protein interactions that lead to cellular senescence and eventually cell death.

The mission of Agent 66, if accepted, is to contact the hitman, Pinky – who then sees to it that the Retinal Ganglion Cell is put to sleep…permanently.

So it appears that we may finally have a mechanism to explain how elevated IOP can result in the death of Retinal Ganglion Cells leading to permanent loss of vision. Why is knowing this mechanism important? Because now that the genes and their associated protein products are known, therapies might be developed to target these pathways. Such therapies could have the potential to slow or halt vision loss even in if the IOP could not be controlled.

But wait, there’s more…

SIX6 and p16INK4a are far from the only genes that have been associated with glaucoma. Many others have been found that are associated with particular families or types of glaucoma. To review them all would test the wakefulness of even the most interested reader. If you’re interested in the alphabet soup of genes associated with glaucoma a quick Google search should quickly overwhelm you.

Related Articles:

1. Central Visual Field Loss Associated with More Rapid Vision Loss in Glaucoma
2. What Does Cellophane Have to Do with Glaucoma?
3. Why Don’t Glaucoma Treatments Totally Halt Vision Loss?
4. Does Everyone With Glaucoma Go Blind?
5. How Common Is Glaucoma?

Don’t delay getting checked for glaucoma.

Make an appointment with an eye doctor in your area now.  If you live in the greater Los Angeles area and would like Dr. Richardson to evaluate your eyes for glaucoma call 626-289-7856 now. No referral required. Appointments are available, Tuesday through Saturday.