Johns Hopkins study reveals enzyme that shields neurons from oxidative stress

New research from Johns Hopkins Medicine shows that the enzyme biliverdin reductase A (BVRA) plays a direct protective role against oxidative stress in neurons, independent of its role producing the yellow pigment bilirubin.

In this study of genetically engineered mice, the scientists say BVRA protected brain cells from oxidative stress, an imbalance between oxidants and antioxidants that protect cells, by modulating another key protein, NRF2, which regulates the levels of protective proteins and antioxidants in cells. Oxidative stress is a hallmark of neurodegenerative diseases, including Alzheimer's disease. 

A report describing the research, funded by the National Institutes of Health, was published Sept. 30 in Proceedings of the National Academy of Sciences.

"Our research identifies BVRA as a key player in cellular defense with profound implications for aging, cognition and neurodegeneration," says Bindu Paul, M.S., Ph.D., associate professor of pharmacology, psychiatry and neuroscience at the Johns Hopkins University School of Medicine, who led the study. 

This role of BVRA could potentially be targeted by drugs to slow the development of neurodegenerative disorders such as Alzheimer's disease."

Solomon H. Snyder, M.D., co-corresponding author, distinguished service professor of neuroscience, pharmacology, and psychiatry

The new research builds on past NIH-funded Johns Hopkins work published in Cell Chemical Biology that indicated how bilirubin serves as an antioxidant in the brains of mice. More recently, in a report published in Science, the pigment was shown to protect against the worst effects of malaria in mice.

In the recent study, scientists first genetically engineered mice to lack genes that make both BVRA and NRF2 proteins. However, none of these mice survived, indicating that together these proteins may have an important interaction.

Next, in mice genetically engineered to lack only BVRA, the scientists say NRF2 malfunctioned, and its target genes produced fewer antioxidants. In cell cultures, the team went on to show that BVRA and NRF2 physically bind, and in doing so regulate genes involved in protecting brain cells. The genes regulated by both proteins include those involved in transportation of oxygen, immune signaling and optimal functioning of mitochondria, the powerhouse of cells.

Importantly, this function did not require BVRA to produce bilirubin. Then, the team of scientists generated mutants of BVRA that could not make bilirubin. The scientists say these mutants retained their ability to regulate 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," says first author Chirag Vasavda, M.D., Ph.D., a physician at Harvard Medical School and Massachusetts General Hospital, who conducted the research as a Johns Hopkins M.D./Ph.D. student. 

"This work highlights the long-term value of mechanistic discovery," says Ruchita Kothari, a graduate student and co-first author of the paper.

"Our research identifies a vital non-canonical of BVRA that plays key roles in neuronal signaling, which may be harnessed for therapeutic benefits," says Paul.

In future experiments, Paul says she aims to evaluate how the BVRA and NRF2 connection goes awry in mouse models of Alzheimer's disease. 

The Johns Hopkins researchers say the study was the result of a sustained, yearslong effort by a team of scientists 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," says Paul.

Funding support for this research was provided by the American Heart Association and Paul Allen Foundation Initiative in Brain Health and Cognitive Impairment, the National Institutes of Health (R01AG071512, R21AG073684, NIH AG077396, NS101967, NS133688, P01CA236778, R01AGs066707, U01 AG073323, P50 DA044123), the Solve-ME foundation, a Catalyst Award from The Johns Hopkins University, the Department of Defense, the Valour Foundation, the Wick Foundation, a Department of Veterans Affairs Merit Award, the Louis Stokes VA Medical Center resources and facilities, the Lincoln Neurotherapeutics Research Fund, the Leonard Krieger Fund of the Cleveland Foundation, the Meisel & Pesses Family Foundation, and an anonymous donor. 

In addition to Paul, Snyder, Vasavda and Kothari, other scientists who contributed to this research are Suwarna Chakraborty, Sunil Jamuna Tripathi, Shruthi Shanmukha, Priyanka Kothari and Adele Snowman from Johns Hopkins; Navneet Ammal Kaidery, Samaneh Saberi, Julia Lefler, Michael C. Ostrowski, Sudarshana Sharma and Bobby Thomas from Medical University of South Carolina, Ryan Dhindsa from Baylor College of Medicine, Kalyani Chaubey and Andrew A. Pieper from Case Western Reserve University School of Medicine, Lakshminarayan Iyer and L. Aravind from NIH; and Eugenio Barone from Sapienza University of Rome.