New research from Johns Hopkins Medicine reveals that the enzyme biliverdin reductase A (BVRA) plays a crucial protective role against oxidative stress in neurons, independent of its traditional function in producing the yellow pigment bilirubin. This discovery, published on September 30 in the Proceedings of the National Academy of Sciences, highlights BVRA’s potential as a therapeutic target for neurodegenerative diseases.
In a study involving genetically engineered mice, researchers demonstrated that BVRA shields brain cells from oxidative stress—an imbalance between oxidants and antioxidants—by interacting with another key protein, NRF2. This protein is responsible for regulating protective proteins and antioxidants within cells. Oxidative stress is notably linked to neurodegenerative diseases such as Alzheimer’s.
Understanding BVRA’s Protective Mechanism
The study, funded by the National Institutes of Health, was led by Bindu Paul, M.S., Ph.D., an associate professor at the Johns Hopkins University School of Medicine. “Our research identifies BVRA as a key player in cellular defense with profound implications for aging, cognition, and neurodegeneration,” Paul stated.
Co-author Solomon H. Snyder, M.D., emphasized the potential for BVRA-targeted drugs to slow the progression of disorders like Alzheimer’s. “This role of BVRA could potentially be targeted by drugs to slow the development of neurodegenerative disorders such as Alzheimer’s disease,” he said.
Historical Context and Previous Research
This groundbreaking research builds on previous NIH-funded studies at Johns Hopkins, which identified bilirubin as an antioxidant in the brains of mice. More recently, bilirubin was shown to mitigate the severe effects of malaria in mice, as reported in Science.
In the latest study, scientists first engineered mice lacking genes for both BVRA and NRF2. The absence of these genes proved lethal, suggesting a critical interaction between the proteins. Further experiments with mice lacking only BVRA showed NRF2 malfunction, resulting in reduced antioxidant production. Cell culture studies revealed that BVRA and NRF2 bind physically, regulating genes crucial for brain cell protection.
Implications for Future Research and Therapeutic Development
Importantly, BVRA’s protective function does not depend on bilirubin production. Mutant BVRA proteins, incapable of producing bilirubin, still regulated NRF2 and protected neurons in mice. “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,” noted first author Chirag Vasavda, M.D., Ph.D.
Ruchita Kothari, a co-first author, highlighted the study’s significance. “This work highlights the long-term value of mechanistic discovery,” she said. Paul added, “Our research identifies a vital non-canonical role of BVRA that plays key roles in neuronal signaling, which may be harnessed for therapeutic benefits.”
Looking Ahead: Future Experiments and Collaborative Efforts
Paul plans to explore how the BVRA and NRF2 connection malfunctions in Alzheimer’s mouse models. The study represents a collaborative effort 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,” Paul remarked.
Funding and Contributions
This research received support from numerous organizations, including the American Heart Association, the Paul Allen Foundation Initiative in Brain Health and Cognitive Impairment, and the National Institutes of Health, among others. The study was a collective endeavor involving scientists from Johns Hopkins, the Medical University of South Carolina, Baylor College of Medicine, Case Western Reserve University, and Sapienza University of Rome.
As the scientific community continues to unravel the complexities of neurodegenerative diseases, the findings on BVRA offer a promising avenue for developing new treatments that could alter the course of these debilitating conditions.
