Researchers Identify a New Mechanism Crucial for Cell Survival in the Eye and Brain

Under the leadership of Nicolas Bazan, MD, Ph.D., Boyd Professor, and Director at LSU Health New Orleans' Neuroscience Center of Excellence, scientists have discovered a novel mechanism that governs a crucial protein essential for cell survival. This mechanism seems to provide protection against the heightened oxidative stress that precedes the onset of neurodegenerative diseases affecting the brain and eyes.

The findings have been published in the journal Cell Death & Disease.

"This discovery goes beyond the commonly studied transcriptional modulation, suggesting its impact on protection against oxidative stress-related diseases and extension of lifespan," notes Dr. Bazan, who is also the Ernest C. and Ivette C. Villere Chair for Retinal Degenerations and Bollinger Family Professor in Alzheimer's Disease. "We found that Elovanoid-34 modulates the activity of the protein, TXNRD1, which is central to the initiation cascade of oxidative stress."

Elovanoid-34 belongs to a category of brain molecules identified by the Bazan lab that coordinate cell-to-cell communication and neuroinflammation-immune activity in response to injury or disease. Elovanoids, derived from omega-3 very long-chain polyunsaturated fatty acids, act as bioactive chemical messengers and are released when cells undergo damage or stress.

The regions affected by ELV-N34 are in close contact with the FAD pocket and the interface zone. The alignment of the peptides with the secondary structure of the TXNRD1 (Fig. S6 and Tables S6–S9) fell into two groups displayed as group A (yellow) and group B (green). The upper left quadrant shows the homodimer 3D (PDB ID: 2ZZC) rendition obtained by X-ray crystallography and available on NCBI (https://www.ncbi.nlm.nih.gov/Structure/icn3d/full.html?&mmdbid=76017&bu=1&showanno=1&source=full-feature). The right upper and the left down quadrants depict the groups A and B highlighted respectively (yellow and green) and the right down quadrant illustrates the whole zone affected by ELV-N34 that in the 3D representation appears as a continuous region. Credit: Cell Death & Disease (2023). DOI: 10.1038/s41419-023-06334-6

Oxidative stress arises from an imbalance between free radicals and the body's antioxidant defenses, potentially resulting in cell and tissue damage and the onset of diseases.

In collaboration with scientists from the Swiss company Biognosys AG, the research team investigated the proteins influenced by Elavamoid-34. Employing proteomics, they examined 130,000 protein sequences corresponding to 4,749 proteins and identified only one protein that underwent structural changes upon interaction with Elovanoid-34.

The researchers pinpointed TXNRD1 as a vital component of the antioxidant system, Glutathione, and a regulator of Ferroptosis, a form of cell death. This discovery is particularly relevant in Age-Related Macular Degeneration, where the support cells for the retina's light-sensitive photoreceptors succumb to excessive oxidative stress conditions.

Elovanoid-34 has the capacity to save retinal pigment epithelial (RPE) cells from undergoing cell death, thereby halting the neurodegeneration of the retina and preventing blindness. In this study, human RPE cells cultivated in the Bazan lab were utilized for experimentation.

"This breakthrough discovery opens new therapeutic avenues for various pathologies and the promotion of successful aging of the nervous system," Dr. Bazan said.

"The gradual decline of functions in aging does engage excessive oxidative stress further magnified by co-morbidities such as diabetes and cardiovascular disorders. In fact, a clear connection is revealed by the present discovery because elovanoids also target neuronal cell senescence and epigenetic signaling. Overall, the protein discovered now to be a site of brain and retina (and likely other organs) protection by elovanoids opens avenues of targeted therapeutics for age-related diseases, stroke, ALS, and traumatic brain injury, as well as to sustain healthy, successful aging,” he conluded.

Reference

Jorgelina M. Calandria et al, Elovanoid-N34 modulates TXNRD1 key in protection against oxidative stress-related diseases, Cell Death & Disease (2023). DOI: 10.1038/s41419-023-06334-6