Seeking Various Vulnerabilities in Regional Areas of the Human Retina

Gabriel Velez, BS

Understanding the distinct features of the fovea, macula, and periphery is crucial in the development of effective targeted treatment therapies for various conditions, including age-related macular degeneration (AMD), cystoid macular edema, retinitis pigmentosa, and diabetic retinopathy.

These areas all serve unique functions, and all are all uniquely vulnerable. In a recent study, researchers examined variations in protein levels in these different regions of the human retina, and how those protein levels affect molecular predisposition for ophthalmic diseases.

“Many vision specialists are aware that certain retinal diseases, such as AMD and diabetic retinopathy, affect different anatomic regions of the retina like the fovea and macula,” Author Gabriel Velez, BS, told MD Magazine. “However, it’s unclear what is happening on the molecular level that makes these regions susceptible to these diseases.”

Velez and his team looked at foveomacular, juxta-macular, and peripheral retina punch biopsies to determine protein levels and identify patterns of expression. They used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure retinal protein levels, and 1-way ANOVA, gene ontology, pathway representation, and network analysis to ascertain protein expression.

Reactive oxygen species (ROS) at elevated levels can cause damage to DNA, proteins, and lipids, and in turn, can lead to apoptosis and genetic dysregulation. Because the retina is the most metabolically active tissue in the human body, it is especially vulnerable to this oxidative stress, particularly when the retina’s natural defenses against these species become less effective with age.

According to the authors, this decline happens throughout the entire retina, but many diseases are more inclined to develop in certain areas.

“In this study, we sought to catalog the thousands of proteins in the normal human retina using proteomics,” Velez said. “A detailed molecular map can give researchers and clinicians clues as to why certain areas of the human retina are more susceptible to different diseases, as well as what therapies may be most effective for treating them. For example, we found that the foveomacular region of the retina contained fewer proteins known to combat oxidative stress in the eye, which may explain why the foveomacular region is susceptible to oxidative damage in diseases like AMD.”

The authors identified “a mean of 1,974 proteins in the foveomacular retina, 1,999 in the juxta-macular retina, and 1,779 in the peripheral retina.” They said that 697 “differentially-expressed proteins included those unique to and abundant in each anatomic region.”

“We also interrogated our proteomics data for retinal antioxidant proteins that could be activated by available drugs and compounds, like ebselen and vitamin B3,” Velez said. “These neuroprotective drugs can be repurposed for different retinal diseases where oxidative stress is a contributing factor, like AMD and diabetic retinopathy."

The authors concluded that they “have developed a reliable and reproducible dissection protocol that makes use of readily available punch biopsy tools. Our focus on analyzing the proteomic profile of different retinal regions provides further insight into their molecular uniqueness and to understanding the pathophysiology of numerous regional retinal diseases.”

The study, “Proteomic analysis of the human retina reveals region-specific susceptibilities to metabolic- and oxidative stress-related diseases,” was published in PLoS One.