Late-onset retinal degeneration mechanism and potential Rx

Late-onset retinal degeneration is an autosomal dominant disorder caused by the substitution of a different amino acid in the protein made by the CTRP5 gene. Earlier discoveries by LSU Health Neuroscience researchers on retina lipids that protect sight helped lay the groundwork for the current study. Their collaborative data suggest a mechanism for the dominant behavior of the CTRP5 gene mutation, which had been unclear.

The protein made by CTRP5 has been identified as a biomarker for obesity and chronic obstructive pulmonary disease, suggesting a role for this protein in regulating cellular fatty acid metabolism. It has been suggested that an enzyme called 5'AMP-activated protein kinase (AMPK) activates CTRP5 to regulate fatty acid metabolism and energy stability. Retinal pigment epithelium (RPE) cells take up photoreceptor outer segments, which have an abundance of fatty acids and lipids.

"Increasing evidence demonstrates that the tips of visual cells that are daily shed in RPE cells convert docosahexaenoic acid (DHA) into Neuroprotectin D1 (NPD1) and other mediators that protect the photoreceptors from photooxidative damage and consequences of mutations such as the one studied here," notes Nicolas Bazan, MD, PhD, Boyd Professor and Director of LSU Health New Orleans Neuroscience Center of Excellence. "AMPK in the RPE itself is a key regulator of the conversion of DHA into protective mediators."

It has been suggested that dysregulation of fatty-acid and lipid metabolism contributes to the atrophy of RPE cells found in age-related macular degeneration. The study found this in cells from patients with late-onset retinal degeneration, as well as reduced secretions of CTRP5. Lower CTRP5 levels are associated with sustained activation of AMPK, which leads to its insensitivity to changes in the cellular energy status.

"Mechanistically, reduced secretion of CTRP5 and predicted lower binding affinity of mutant CTRP5 to the receptor for the gene that makes lipoproteins that carry fats in the bloodstream is the likely reason for the genetically dominant behavior of this disease," says Dr. Bazan, who also holds the Ernest C. and Yvette C. Villere Chair for the Study of Retinal Degeneration.

The researchers demonstrated that a gene therapy approach -- overexpressing CTRP5 -- overcame lower levels of CTRP5 secretion in the cells of patients with late-onset retinal degeneration. They also tested the anti-diabetic drug metformin to determine if it influenced AMPK activity and could reverse RPE deterioration. Metformin has been shown to delay retinal degeneration in mice and to protect the RPE. The researchers found that metformin was effective in re-sensitizing AMPK to changes in cellular stress, restoring energy stability, and alleviating the disease's cellular phenotypes.

Bazan concludes, "The study offers novel insights into the role of CTRP5 in the RPE and how the pathogenic variant in late-onset retinal degeneration causes dominant disease and provides further evidence that metformin can be a beneficial intervention for its treatment."

The LSU Health New Orleans researchers also include Drs. Bokkyoo Jun, Khanh V. Do, Marie-Audrey Kautzman Guerin, and Jorgelina Calandria, of the Neuroscience Center of Excellence. Other authors were from the National Eye Institute and the University of Pennsylvania.

The research was supported by the National Eye Institute of the National Institutes of Health and the Eye Ear Nose Throat (EENT) Foundation of New Orleans.