Researchers at Oregon Health & Science University have pinpointed specific sites on NMDA receptors targeted by harmful antibodies in a rare autoimmune brain disorder known as "Brain on Fire." This discovery, published in Science Advances, could lead to more precise treatments and earlier detection. The condition affects about 1 in 1 million people annually, mainly young adults, causing severe symptoms like seizures and memory loss.
The autoimmune disorder, popularized by the memoir and 2016 film "Brain on Fire," occurs when the immune system attacks NMDA receptors essential for memory and thinking. This leads to anti-NMDA receptor autoantibodies that trigger psychiatric symptoms, seizures, personality changes, profound memory loss, and potentially death in severe cases.
In a study led by Junhoe Kim, Ph.D., a postdoctoral fellow at the OHSU Vollum Institute, scientists used a mouse model to analyze these autoantibodies. They identified precise binding locations on a subunit of the NMDA receptor, which closely matched sites observed in human patients. "We have really solid evidence because the autoantibody binding sites that Junhoe identified overlap with those from people," said senior author Eric Gouaux, Ph.D., a senior scientist at the Vollum Institute and Howard Hughes Medical Institute investigator.
Advanced near-atomic imaging at the Pacific Northwest Cryo-EM Center revealed that nearly all antibodies targeted a single domain of the receptor. "Nearly all of the antibodies bound to a single domain of the receptor that happens to be the part of the receptor that's simplest to target," Gouaux noted. Kim added that prior research had identified a general region, but their work specified the exact binding sites using the full panel of autoantibodies from the mouse model.
Co-author Gary Westbrook, M.D., a neurologist at the Vollum Institute, highlighted the potential for pharmaceutical development. The finding could enable drugs that block these interactions more precisely than current immunosuppression therapies, which do not work for all patients and risk relapses. The research team also included Farzad Jalali-Yazdi, Ph.D., and Brian Jones, Ph.D., from OHSU.
The study appears in Science Advances (2026; 12 (3)), with support from the National Institutes of Health and others.
