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 the yellow pigment bilirubin but also directly shields neurons from oxidative stress. This discovery, published on September 30 in the Proceedings of the National Academy of Sciences, highlights BVRA’s potential as a target for therapeutic interventions in neurodegenerative diseases like Alzheimer’s.
The study, conducted on genetically engineered mice, demonstrates that BVRA protects brain cells by modulating the protein NRF2, which governs the levels of protective proteins and antioxidants. Oxidative stress, an imbalance between oxidants and antioxidants, is a known hallmark of neurodegenerative diseases, making this research particularly significant.
Unveiling BVRA’s Protective Mechanism
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.” The study reveals that BVRA’s protective role is independent of its bilirubin-producing function.
Co-corresponding author Solomon H. Snyder, M.D., emphasized the potential therapeutic applications, stating, “This role of BVRA could potentially be targeted by drugs to slow the development of neurodegenerative disorders such as Alzheimer’s disease.”
Building on Previous Discoveries
This research builds upon earlier studies funded by the National Institutes of Health (NIH) that explored bilirubin’s antioxidant properties in the brain. A previous report in Science demonstrated bilirubin’s protective effects against malaria in mice, further underscoring the pigment’s biological significance.
In the recent study, the researchers engineered mice to lack both BVRA and NRF2 genes. The absence of these genes proved fatal, suggesting a critical interaction between the two proteins. Further experiments showed that without BVRA, NRF2 malfunctioned, leading to reduced antioxidant production. The team discovered that BVRA and NRF2 physically bind to regulate genes involved in oxygen transport, immune signaling, and mitochondrial function.
Implications for Neurodegenerative Diseases
The findings suggest that BVRA’s role extends beyond bilirubin production. As first author Chirag Vasavda, M.D., Ph.D., highlighted, “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.”
The research team generated BVRA mutants incapable of producing bilirubin, yet these mutants retained their ability to regulate NRF2 and protect neurons. This discovery opens new avenues for drug development targeting BVRA’s non-canonical functions.
Future Research Directions
Looking ahead, Paul plans to investigate how the BVRA-NRF2 interaction may be disrupted in Alzheimer’s disease models. The study represents a culmination of years of collaborative research across multiple institutions, integrating expertise in neuroscience, biochemistry, genomics, and clinical medicine.
“Our efforts underscore the power of multidisciplinary collaboration fueled by long-term investment in scientific research to address complex biological challenges,” said Paul.
Funding and Collaborative Efforts
The research received extensive support from various institutions, including the American Heart Association, the Paul Allen Foundation Initiative in Brain Health and Cognitive Impairment, and the National Institutes of Health. Additional funding came from organizations such as the Solve-ME Foundation, the Department of Defense, and several foundations and awards.
In addition to Paul, Snyder, Vasavda, and Kothari, the research team included scientists from Johns Hopkins, the Medical University of South Carolina, Baylor College of Medicine, Case Western Reserve University School of Medicine, the NIH, and Sapienza University of Rome.
This groundbreaking study not only enhances our understanding of BVRA’s role in neuroprotection but also sets the stage for future research aimed at combating neurodegenerative diseases through innovative therapeutic strategies.
