New research from Johns Hopkins Medicine has unveiled a groundbreaking discovery regarding the enzyme biliverdin reductase A (BVRA). The study reveals that BVRA plays a crucial protective role against oxidative stress in neurons, independent of its known function in producing the yellow pigment bilirubin. This finding could have significant implications for treating neurodegenerative diseases such as Alzheimer’s.
The study, conducted on genetically engineered mice, demonstrated that BVRA safeguards brain cells from oxidative stress by modulating another vital protein, NRF2. This protein is responsible for regulating the levels of protective proteins and antioxidants within cells. The research, funded by the National Institutes of Health, was published on September 30 in the Proceedings of the National Academy of Sciences.
Understanding Oxidative Stress and Neurodegeneration
Oxidative stress, an imbalance between oxidants and antioxidants, is a hallmark of neurodegenerative diseases, including Alzheimer’s. The Johns Hopkins study highlights BVRA’s role in mitigating this stress by interacting with NRF2. According to Bindu Paul, M.S., Ph.D., 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.”
Solomon H. Snyder, M.D., co-corresponding author and distinguished service professor of neuroscience, pharmacology, and psychiatry, emphasized the potential therapeutic applications of this discovery. “This role of BVRA could potentially be targeted by drugs to slow the development of neurodegenerative disorders such as Alzheimer’s disease,” he noted.
Building on Previous Research
This new research builds on earlier work by Johns Hopkins, also funded by the NIH, which was published in Cell Chemical Biology. That study indicated bilirubin’s role as an antioxidant in the brains of mice. More recently, bilirubin was shown to protect against severe effects of malaria in mice, as reported in Science.
In the current study, scientists initially engineered mice to lack genes producing both BVRA and NRF2 proteins. The result was that none of these mice survived, suggesting a critical interaction between these proteins. Subsequently, in mice lacking only BVRA, NRF2 malfunctioned, leading to reduced antioxidant production. The research further demonstrated that BVRA and NRF2 physically bind to regulate genes protecting brain cells.
Mechanistic Insights and Future Directions
Importantly, the protective function of BVRA does not rely on bilirubin production. The team created BVRA mutants unable to produce bilirubin, yet these mutants retained their ability to regulate NRF2 and protect neurons. Chirag Vasavda, M.D., Ph.D., a physician at Harvard Medical School and Massachusetts General Hospital, stated, “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.”
Ruchita Kothari, a graduate student and co-first author, added, “This work highlights the long-term value of mechanistic discovery.” Bindu Paul concluded, “Our research identifies a vital non-canonical role of BVRA that plays key roles in neuronal signaling, which may be harnessed for therapeutic benefits.”
Collaborative Efforts and Funding
The study represents a sustained, yearslong effort by a multidisciplinary team of scientists from 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 support for this research was extensive, including contributions from the American Heart Association, the Paul Allen Foundation Initiative in Brain Health and Cognitive Impairment, and several NIH grants, among others. The collaboration involved researchers from Johns Hopkins, the Medical University of South Carolina, Baylor College of Medicine, Case Western Reserve University School of Medicine, NIH, and Sapienza University of Rome.
Looking ahead, the researchers plan to explore how the BVRA and NRF2 connection may malfunction in mouse models of Alzheimer’s disease, potentially paving the way for new therapeutic strategies.
