Protein Found To Protect Brain Cells Most Impacted by Glaucoma

Researchers in Georgia report that sigma 1 receptor, a ubiquitous protein known to protect cells from stress, also appears to protect the neurons most impacted by glaucoma, a major cause of blindness. The findings, published recently in Investigative Ophthalmology and Visual Science, provide some of the first evidence that increasingly available synthetic compounds like the pain reliever (+) - pentazocine, which activate sigma 1 receptor, may one day help mitigate damage from glaucoma and other diseases.

“Unfortunately in patients who have glaucoma, because of the structure of the retina and the optic nerve, the axons, or extensions, of the retinal ganglion cells are vulnerable to damage,” says Dr. Kathryn Bollinger, an ophthalmologist specializing in glaucoma and a retinal cell biologist in the Department of Ophthalmology at the Medical College of Georgia (MCG). “Since these cells are so important for communicating the visual signals to the brain, patients can lose some or all their vision because of glaucomatous damage.” The blood vessel system that feeds that back area of the optic nerve also can become damaged, and inflammation can worsen damage, she adds.

Sigma 1 receptors are expressed on cells throughout the body, including the retinal ganglion cells in the back of the eye, which help connect the eye to the brain so we can see, as well as brain cells called astrocytes that normally nourish and support those neurons.  The MCG team found that, when retinal ganglion cells and astrocytes are in a cell culture dish together, retinal ganglion cells survived fairly well, unless the sigma 1 receptor is missing from their astrocytes.  

The benefits they saw in culture were apparent even though the two cell types were not physically connected—they were just in the same dish. Normally, star-shaped astrocytes have a pretty tight hold on the neurons they are supporting.

While more work is needed, these and previous findings indicate sigma 1 receptor enables astrocytes to secrete supportive factors for neurons like brain-derived neurotrophic factor.  In fact, they found that retinal ganglion cells are better protected from just being in the same medium in which astrocytes with their sigma 1 receptors intact had been, even after the astrocytes themselves were not present.  But when the internal receptor was missing from astrocytes, neuroprotection retinal ganglion cells grew fewer and shorter neurites—extensions neurons use to reach out to other neurons and an indicator of their overall health and function. They also experienced increased apoptosis, which is one way in which the body eliminates cells that no longer function properly. 

“It speaks to factors that are released, but to see a difference in the absence of sigma receptor makes you really think what else is this little magical protein governing that is now lost,” notes co-author Dr. Sylvia Smith, retinal cell biologist and chair of the MCG Department of Cellular Biology and Anatomy, a pioneer in exploring the neuroprotective benefits of sigma 1 receptor in the eye.  

Smith’s lab has led studies showing that (+) - pentazocine can help protect retinal ganglion cells in models of conditions like diabetic retinopathy, where the retina is a target. In 2008, Smith and her colleagues published the first evidence of the dramatic effects of the sigma 1 receptor ligand on protecting the retina in diabetic retinopathy, and suggested then that it may also be helpful for glaucoma. Retinal ganglion cells are compromised in both conditions.

They also have evidence that activating sigma 1 receptor increases the activity of the synapses on the optic nerve head, including an increase in STAT3, a protein essential to many cell functions and known to regulate the reactivity of astrocytes. They note that in some disease states, like Alzheimer’s and multiple sclerosis, inhibiting STAT3 activation in astrocytes provides neuroprotection. More study is needed on the how activating or inhibiting sigma 1 receptor alters STAT3 levels and how each impact retinal ganglion cell survival.

Additional compounds that activate sigma 1 receptor are in varying stages of development for a wide range of disorders from neurodegenerative diseases like Alzheimer’s to cancer to severe acute respiratory syndrome resulting from COVID-19. The increasing availability of compounds that activate sigma 1 receptors makes clinical application easier if beneficial findings continue to hold, Bollinger says. “This is a target that appears to be clinically useful from a practical point of view,” she adds.

Bollinger and colleagues are now further exploring any neuroprotective role sigma 1 receptors have in each brain cell type, how they might work together, and what happens when it is the retinal ganglion cells missing sigma 1 receptor. They also are working to move their studies from cell culture into animal models for glaucoma.