Antioxidant defense system in the brain discovered

Summary: A new study identifies biliverdin reductase A (BVRA) as a crucial enzyme that defends neurons from oxidative stress, acting independently of its traditional role in bilirubin production. Using genetically modified mice, the researchers discovered that BVRA directly binds to NRF2, a master regulator of antioxidant defense, ensuring the activation of protective genes that maintain cellular health.

Even when BVRA’s ability to produce bilirubin was removed, it still retained neuronal resilience, highlighting a separate and essential role in brain protection. The findings open new therapeutic possibilities for targeting BVRA to combat neurodegenerative disorders such as Alzheimer’s disease.

Key facts

Independent protection: BVRA protects neurons through direct interaction with NRF2, not through bilirubin synthesis. Neurodegenerative link: Disruption of BVRA function affected antioxidant gene activity, suggesting a role in diseases such as Alzheimer’s. Therapeutic potential: Targeting the newly discovered mechanism of BVRA may strengthen brain defense systems against oxidative damage.

Source: JHU

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 in the production of the yellow pigment bilirubin.

In this study of genetically modified mice, 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 September 30 in the 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 function of BVRA could potentially be targeted by medications to slow the development of neurodegenerative disorders such as Alzheimer’s disease,” says co-corresponding author Solomon H. Snyder, MD, distinguished professor of neuroscience, pharmacology, and psychiatry.

The new research builds on earlier NIH-funded Johns Hopkins work published in Cell Chemical Biology, which indicated how bilirubin acts 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 for the first time genetically engineered mice to lack genes that produce the 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 did not function properly and its target genes produced fewer antioxidants. In cell cultures, the team showed 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 oxygen transport, immune signaling and the optimal functioning of mitochondria, the powerhouse of cells.

Importantly, this function did not require BVRA to produce bilirubin. The team of scientists then generated BVRA mutants that could not produce 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 an MD/Ph.D. from Johns Hopkins. student.

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

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

In future experiments, Paul says his goal is to evaluate how the BVRA and NRF2 connection fails in mouse models of Alzheimer’s disease.

Johns Hopkins researchers say the study was the result of a sustained, years-long effort by a team of scientists from multiple institutions, integrating expertise in neuroscience, biochemistry, genomics and clinical medicine.

“Our efforts underscore the power of multidisciplinary collaboration driven by long-term investment in scientific research to address complex biological challenges,” says Paul.

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

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

About this neuroscience research news

Author: Alexandria Carolan
Source: JHU
Contact: Alexandria Carolan – JHU
Image: Image is credited to Neuroscience News.

Original research: Open access.
“Biliverdin reductase A is an important determinant of NRF2 protective signaling” by Bindu Paul et al. PNAS

Abstract

Biliverdin reductase A is an important determinant of protective NRF2 signaling

Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates bilirubin, a neuroprotective and lipophilic antioxidant.

Here, we identify a non-enzymatic role for BVRA in redox regulation. Through phylogenetic, genetic, biochemical, and enzymatic assays, we found that BVRA exerts critical non-enzymatic antioxidant activity.

Transcriptomic analyzes further revealed that BVRA physically and genetically interacts with nuclear factor erythroid-derived type 2 (NRF2), an important transcriptional regulator of cellular redox signaling.

ChIP-seq and RNA-seq analyzes reveal that BVRA and NRF2 coordinate the expression of antioxidant genes, many of which are normally dysregulated in neurodegenerative conditions such as Alzheimer’s disease. Therefore, this non-canonical BVRA-NRF2 axis controls an essential redox signaling pathway in neuroprotection.

Our findings position BVRA as a dual-function integrator of antioxidant defense in the lipophilic and hydrophilic compartments, bridging these two distinct modes of redox protection in the brain.