Wert Shows Eye Protein Protects from Oxidative Stress

Palo Alto, CA — Patients with diabetes suffer ongoing damage to their retina that can result in blindness. Oxidative chemicals produced in the eye are a key factor. 

Katherine Wert Ph.D., a postdoctoral fellow in the Mahajan Laboratory, searched for antioxidant proteins in the human eye and found a critical enzyme that protects the retina. Discovery of the antioxidant SOD3 enzyme may lead to better treatments for diabetic retinopathy.

The human body actively balances the production of free radicals, harmful radical oxygen species, and the beneficial antioxidants that keep them in check. When this balance is disrupted, a build-up of free radicals results in oxidative stress and tissue damage.

Dr. Wert noted, “The human eye, particularly the light-sensing retina, is highly sensitive to changes in oxidative stress and metabolic waste. Oxidative stress has also been linked to macular degeneration, cataracts, uveitis and corneal inflammation.”

To find the critical antioxidant protein, the researchers scanned their large protein database of human vitreous, the gel that fills the inside of the eye. They identified a protein named superoxide dismutase-3 (SOD3) that localized to unique regions in the vitreous gel, right next to the retina.

Next, in collaboration with Professor Richard Domann and researchers in the Free Radical and Radiation Biology Program at the University of Iowa, they analyzed eyes from engineered mice missing the SOD3 enzyme. Although the eyes appeared normal, mice without SOD3 had elevated levels of highly specific oxidative stress biomarkers in their vitreous. The same oxidative stress biomarkers were found in the vitreous of human diabetic patients.

“We have a great collaboration with Dr. Domann and his skilled colleagues,” Mahajan said. “Measuring oxidative stress biomarkers in the tiny volumes of fluid from mice and from human patients is incredibly challenging biochemistry.” 

Co-author McAnany at the University of Illinois found that diabetic patients can show a specific diminished retinal response to light. In collaboration with Matthew Harper at the University Iowa, experiments in humans revealed an identical diminished retinal response in mice missing SOD3. Experiments performed by Dr. Wert suggested that an antioxidant drug might reverse the visual signaling abnormalities. 

Dr. Alexander Bassuk, a collaborator at the University of Iowa, summarized, “The absence or dysregulation of the vitreous SOD3 antioxidant increases oxidative stress and tissue damage to the inner retina, and this may be an important target to treat diabetic and other vitreoretinal diseases.”

Caption: Understanding how retinal cells regulate oxidative stress and metabolic waste will open opportunities to explore new eye therapies.