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| Using near-atomic imaging, OHSU researchers mapped where disease-associated autoantibodies bind to the extracellular domain of the NMDA receptor. The highlighted region — colored yellow through red, based on how frequently it is targeted — reveals small areas of the receptor recognized by autoantibodies in both mice and people with anti-NMDAR encephalitis, making it a promising target for future treatments. Photo Credit: OHSU/Christine Torres Hicks |
Scientific Frontline: Extended "At a Glance" Summary
The Core Concept: Researchers have identified specific "hot spots" on the NMDA receptor where disease-causing autoantibodies bind, pinpointing a precise target for treating the autoimmune condition often called "Brain on Fire" (anti-NMDA receptor encephalitis).
Key Distinction/Mechanism: Current treatments rely on broad immunosuppression, which can be inconsistent and cause significant side effects. This discovery uses near-atomic imaging to map the exact locations on the receptor's extracellular domain where the attack occurs. By identifying these specific binding sites, scientists aim to develop therapies that block the autoantibodies directly rather than suppressing the entire immune system.
Origin/History: The study was published on January 14, 2026, in the journal Science Advances by a team at Oregon Health & Science University (OHSU).
Major Frameworks/Components:
- NMDA Receptor: A critical neurotransmitter receptor in the brain responsible for memory and learning, which becomes the target of the autoimmune attack.
- Cryo-Electron Microscopy (Cryo-EM): The high-resolution imaging technology used to visualize the receptor and antibody interactions at a near-atomic level.
- Comparative Modeling: Researchers confirmed the relevance of their findings by matching autoantibody binding sites in engineered mice with those found in human patients.
Why It Matters: This discovery opens the door to the first targeted drug therapies for anti-NMDA receptor encephalitis, potentially offering a cure that prevents relapse and avoids the risks of long-term immunosuppression. Additionally, these specific markers could lead to blood tests that allow for earlier diagnosis and intervention.
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| Using near-atomic imaging, OHSU researchers mapped where disease-associated autoantibodies bind to the extracellular domain of the NMDA receptor. The highlighted region — colored yellow through red, based on how frequently it is targeted — reveals small areas of the receptor recognized by autoantibodies in both mice and people with anti-NMDAR encephalitis, making it a promising target for future treatments. Photo Credit: OHSU/Christine Torres Hicks |
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 condition may be best known by the bestselling autobiography and 2016 motion picture, “Brain on Fire.” The condition is considered a rare disorder affecting about one in 1 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.
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| Junhoe Kim, Ph.D. (OHSU) Photo Credit: Courtesy of Oregon Health & Science University |
In the study published today, researchers identified specific sites on a subunit of the NMDA receptor that, if they could be blocked, may potentially reverse the progression of the disease. Lead author Junhoe Kim, Ph.D., a postdoctoral fellow in the Gouaux lab in the OHSU Vollum Institute, examined anti-NMDA receptor autoantibodies from a mouse model that OHSU researchers 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.
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| Eric Gouaux, Ph.D. (OHSU) Photo Credit: Courtesy of Oregon Health & Science University |
“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 at the OHSU Vollum Institute 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 with 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 the state-of-the art imaging technology. It’s operated jointly by OHSU and the Pacific Northwest National Laboratory, and funded by the National Institutes of Health.
“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.”
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| Gary Westbrook, M.D. (OHSU) Photo Credit: Courtesy of Oregon Health & Science University |
Co-author Gary Westbrook, M.D., a neurologist and senior scientist in the OHSU 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.
All research involving animal subjects at OHSU must be reviewed and approved by the university’s Institutional Animal Care and Use Committee (IACUC). The IACUC’s priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.
Published in journal: Science Advances
Authors: Junhoe Kim, Farzad Jalali-Yazdi, Brian E. Jones, Gary L. Westbrook, and Eric Gouaux
Source/Credit: Oregon Health & Science University | Erik Robinson
Reference Number: ns011426_01
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