Summary: Researchers made a pivotal discovery in neuroprotection. They identified how Elovanoid-34, a molecule in the brain, modulates the protein TXNRD1 to combat oxidative stress, a precursor to neurodegenerative diseases.
This breakthrough reveals that Elovanoid-34 can prevent cell death in conditions like Age-Related Macular Degeneration by regulating oxidative stress.
The study emphasizes the potential of this discovery for developing new therapies for age-related diseases and promoting successful nervous system aging.
- Elovanoid-34, found in the brain, plays a crucial role in controlling the protein TXNRD1, which is essential in managing oxidative stress.
- This discovery offers potential new treatments for neurodegenerative diseases and conditions like Age-Related Macular Degeneration.
- The research, supported by the National Eye Institute and the Eye, Ear, Nose & Throat Foundation, opens new avenues for understanding aging and developing targeted therapeutics for various age-related diseases.
Scientists at LSU Health New Orleans’ Neuroscience Center of Excellence, led by Nicolas Bazan, MD, PhD, Boyd Professor and Director, have identified a new mechanism that regulates a protein key for cell survival.
It appears to protect against the excessive oxidative stress that precedes the development of neurodegenerative diseases of the brain and eye.
Results are published in the Nature 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 is part of a class of molecules in the brain discovered by the Bazan lab that synchronize cell-to-cell communication and neuroinflammation-immune activity in response to injury or disease.
Elovanoids are bioactive chemical messengers made from omega-3 very long-chain polyunsaturated fatty acids. They are released on demand when cells are damaged or stressed.
Oxidative stress occurs when there is an imbalance between free radicals and antioxidant defenses to detoxify them. It can lead to cell and tissue damage and the onset of diseases.
The research team, which included scientists from the Swiss company Biognosys AG, identified the proteins affected by Elavamoid-34. Using proteomics, they screened 130,000 protein sequences corresponding to 4,749 proteins and discovered that only one changed in structure upon contact with Elovanoid-34.
Researchers found that TXNRD1 is a crucial component of the antioxidant system, Glutathione, and targets a regulator of Ferroptosis, a type of cell death. This is particularly the case in Age-Related Macular Degeneration where the support cells of the photoreceptors of the light in the retina succumb to excessive oxidative stress conditions.
These cells, called retinal pigment epithelial (RPE) cells, can be rescued from death by Elovanoid-34, stopping the neurodegeneration of the retina and blindness. The current study uses human RPE cells, which were developed in the Bazan lab.
“This breakthrough discovery opens new therapeutic avenues for various pathologies and the promotion of successful aging of the nervous system,” concludes Dr. Bazan.
LSU Health New Orleans Neuroscience Center co-authors also included Drs. Jorgelina Calandria, Surjyadipta Bhattacharjee, Sayantani Kala-Bhattacharjee, and Pranab K. Mukherjee. Co-authors from Biognosys AG included Yuehan Feng, Jakob Vowinckel and Tobias Treiber.
The research was supported by a grant from the National Eye Institute of the National Institutes of Health and the Eye, Ear, Nose & Throat Foundation in New Orleans.
“The present discovery opens a new dimension to understanding the complex multifactorial process of aging,” adds Dr. Bazan.
“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.”
About this genetics, neurology, and aging research news
Author: Leslie Capo
Contact: Leslie Capo – LSU
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Elovanoid-N34 modulates TXNRD1 key in protection against oxidative stress-related diseases” by Nicolas Bazan. Cell Death and Disease
Elovanoid-N34 modulates TXNRD1 key in protection against oxidative stress-related diseases
The thioredoxin (TXN) system is an NADPH + H+/FAD redox-triggered effector that sustains homeostasis, bioenergetics, detoxifying drug networks, and cell survival in oxidative stress-related diseases.
Elovanoid (ELV)-N34 is an endogenously formed lipid mediator in neural cells from omega-3 fatty acid precursors that modulate neuroinflammation and senescence gene programming when reduction-oxidation (redox) homeostasis is disrupted, enhancing cell survival.
Limited proteolysis (LiP) screening of human retinal pigment epithelial (RPE) cells identified TXNRD1 isoforms 2, 3, or 5, the reductase of the TXN system, as an intracellular target of ELV-N34. TXNRD1 silencing confirmed that the ELV-N34 target was isoform 2 or 3.
This lipid mediator induces TXNRD1 structure changes that modify the FAD interface domain, leading to its activity modulation. The addition of ELV-N34 decreased membrane and cytosolic TXNRD1 activity, suggesting localizations for the targeted reductase.
These results show for the first time that the lipid mediator ELV-N34 directly modulates TXNRD1 activity, underling its protection in several pathologies when uncompensated oxidative stress (UOS) evolves.
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