New research from Johns Hopkins Medicine has unveiled a surprising dual role for the enzyme biliverdin reductase A (BVRA), which not only contributes to the production of bilirubin but also protects neurons from oxidative stress. This discovery could have significant implications for understanding and potentially treating neurodegenerative diseases such as Alzheimer’s.
The study, conducted on genetically engineered mice, revealed that BVRA safeguards brain cells by modulating the protein NRF2, which is crucial for regulating protective proteins and antioxidants within cells. Oxidative stress, an imbalance between oxidants and antioxidants, is a known hallmark of neurodegenerative conditions.
Published in the Proceedings of the National Academy of Sciences on September 30, this research was funded by the National Institutes of Health. According to Bindu Paul, M.S., Ph.D., associate professor at Johns Hopkins University School of Medicine and lead author of the study,
“Our research identifies BVRA as a key player in cellular defense with profound implications for aging, cognition, and neurodegeneration.”
Understanding BVRA’s Protective Role
The study builds on previous work by Johns Hopkins researchers, which demonstrated bilirubin’s antioxidant properties in the brain. More recent findings published in Science showed bilirubin’s protective effects against malaria in mice.
In their latest research, scientists engineered mice lacking the genes for both BVRA and NRF2, none of which survived, suggesting a critical interaction between these proteins. Mice lacking only BVRA exhibited malfunctioning NRF2 and reduced antioxidant production. Further experiments confirmed that BVRA and NRF2 physically bind to regulate genes crucial for brain cell protection, including those involved in oxygen transport, immune signaling, and mitochondrial function.
Importantly, this protective function of BVRA does not depend on bilirubin production. Mutant BVRA proteins incapable of producing bilirubin still retained the ability to regulate NRF2 and protect neurons.
Potential Therapeutic Implications
The discovery of BVRA’s dual role opens new avenues for therapeutic interventions targeting neurodegenerative diseases. Co-corresponding author Solomon H. Snyder, M.D., emphasized the potential for drug development, stating,
“This role of BVRA could potentially be targeted by drugs to slow the development of neurodegenerative disorders such as Alzheimer’s disease.”
Chirag Vasavda, M.D., Ph.D., a physician at Harvard Medical School and Massachusetts General Hospital, and first author of the study, highlighted the broader significance of their findings:
“This work shows that BVRA does more than produce bilirubin, and is actually a molecular integrator of key cellular processes that help protect neurons from damage.”
Future Research Directions
Looking ahead, Bindu Paul plans to explore how the BVRA-NRF2 interaction might malfunction in Alzheimer’s disease models. This research underscores the importance of multidisciplinary collaboration and long-term scientific investment, as noted by Paul:
“Our efforts underscore the power of multidisciplinary collaboration fueled by long-term investment in scientific research to address complex biological challenges.”
The study was a collaborative effort involving scientists from Johns Hopkins, the Medical University of South Carolina, Baylor College of Medicine, Case Western Reserve University, and Sapienza University of Rome. Funding was provided by a variety of sources, including the American Heart Association, the National Institutes of Health, and the Department of Defense, among others.
As research continues to unravel the complexities of BVRA’s functions, the potential for developing new treatments for neurodegenerative diseases grows stronger. This breakthrough not only highlights the enzyme’s unexpected protective role but also sets the stage for future innovations in brain health.
