A new study published in Science Advances describes a potential target for therapies aimed at treating anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, also known as ‘Brain on Fire,’ an autoimmune disorder that is triggered by an attack on the NMDA receptor in the brain. Besides developing more effective therapies, the scientists also believe that their work could make it possible to design a blood test capable of detecting the condition earlier so that patients can start treatment sooner.
Details of the work are published in a paper titled “Cryo-EM of autoantibody-bound NMDA receptors reveals antigenic hot spots in an active immunization model of anti-NMDAR encephalitis.” The scientists leading the study are from Oregon Health and Science University (OSHU).
According to the paper, the scientists used cryo-electron microscopy to identify specific sites on a subunit of the NMDA receptor that, if blocked, could potentially reverse the progression of the disease. The autoimmune attack on the NMDA receptor that kicks off the condition is mediated in part by anti-NMDAR autoantibodies. When Junhoe Kim, PhD, a postdoctoral fellow in the Vollum Institute at OSHU and lead author on the study, compared images of anti-NMDAR autoantibodies from a mouse model of the disease to images from the same autoantibodies isolated from people with the disease, he found that the binding sites matched.
This insight gave scientists a clear starting point. “From previous studies, people knew where the antibodies might bind,” Kim 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.”
Specifically, the scientists found that “native autoantibodies recognized two distinct binding sites on the GluN1 amino-terminal domain, which we confirmed using monoclonal antibodies bound to native NMDARs purified from mouse brain.” Then, “structural analysis of autoantibody-bound NMDAR complexes identified antigenic hotspots within the GluN1 amino-terminal domain” that “provide potential targets for therapeutic intervention,” they wrote.
Essentially, “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,” said Eric Gouaux, PhD, senior scientist at Vollum and an investigator with the Howard Hughes Medical Institute. “It’s a super exciting result, actually.”
Currently, patients with anti-NMDAR encephalitis are typically treated with immunotherapies that are non-specific and patients can relapse, according to Gary Westbrook, MD, a co-author on the study and a neurologist and senior scientist in the Vollum Institute. “More specific approaches are definitely needed,” he said. That could include designing “small molecules or engineered proteins … to compete with autoantibodies by occupying the same receptor surface,” the scientists wrote in Science Advances. “Alternatively, such molecules could bind directly to the autoantibodies, preventing their association with the receptor and thereby mitigating downstream pathogenic effects.”
