HMN 2026: How Near-atomic imaging reveals promising target for ‘Brain on Fire’ condition

Scientists have identified a promising target for treatment of a devastating autoimmune disease affecting the brain.

The discovery could lead to the development of new therapies for a disease triggered by an attack on one of the key neurotransmitter receptors in the brain, the NMDA receptor. It also raises the potential for a blood test to detect a signal of the condition and enable earlier treatment with existing therapies.

The study from Oregon Health & Science University is published in Science Advances.

The condition may be best known by the bestselling autobiography and the 2016 motion picture, “Brain on Fire.” The condition is considered a rare disorder affecting about 1 in a million people annually, predominantly people in their 20s and 30s.

The condition is triggered by an autoimmune attack on the brain’s NMDA receptor, mediated in part by anti-NMDA receptor autoantibodies, and is characterized by intellectual changes, severe memory loss, seizures and even death.

New research uncovers antibody binding sites

In the new study, researchers identified specific sites on a subunit of the NMDA receptor that—if they could be blocked—could potentially reverse the progression of the disease. Lead author Junhoe Kim, Ph.D., a postdoctoral fellow in the OHSU Vollum Institute, examined anti-NMDA receptor autoantibodies from a mouse model that OHSU researchers had previously engineered for the purpose. He then compared it with images from the same autoantibodies isolated from people affected by the disease.

The location of the binding sites in the mouse model matched those in people afflicted with the condition.

“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., senior scientist in the Vollum and an investigator with the Howard Hughes Medical Institute. “We’re focused now on this area as literally a hot spot for the interaction that underpins at least one component of the disease.”

Kim said researchers knew generally where to look.

“From previous studies, people knew where the antibodies might bind,” he said. “But we collected the entire native autoimmune antibody panel from a mouse model of the disease, and we elucidated where specifically they bind onto the receptor.”

They made the discovery using near-atomic imaging at the Pacific Northwest Cryo-EM Center, housed at OHSU’s South Waterfront campus and one of three national centers for state-of-the-art imaging technology.

“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 said. “It’s a super exciting result, actually.”

Potential for new therapies and diagnostics

Co-author Gary Westbrook, M.D., a neurologist and senior scientist in the Vollum Institute, said the discovery may clear the way for drug companies to develop a therapeutic agent that could specifically target the binding sites causing the disease. Current therapies involving immunosuppression don’t always work and patients can relapse, he said.

“More specific approaches are definitely needed,” he said.

In addition to Kim, Gouaux and Westbrook, co-authors included Farzad Jalali-Yazdi, Ph.D., and Brian Jones, Ph.D., of OHSU.

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