Cryo-EM of autoantibody-bound NMDA receptors reveals antigenic hotspots in an active immunization model of anti-NMDAR encephalitis
Year: 2026
Type: article
Abstract: -methyl-d-aspartate receptor (NMDAR) encephalitis, a prototype of these autoimmune synaptic disorders, is unexpectedly common. Unfortunately, how the native repertoire of anti-NMDAR autoantibodies recognizes NMDARs and the precise locations of antigenic epitopes remain poorly understood. Here, we used an active immunization model that closely mimics the human disease to immunize adult mice with intact GluN1/GluN2A receptors, resulting in fulminant autoimmune encephalitis. Serum was collected at 6 weeks postimmunization for single-particle cryo-electron microscopy of GluN1/GluN2A receptors complexed with purified polyclonal anti-NMDAR autoantibody fragments. 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. Structural analysis of autoantibody-bound NMDAR complexes identified antigenic hotspots within the GluN1 amino-terminal domain. These hotspots provide potential targets for therapeutic intervention.
Source: Science Advances
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
Awards: High Performance Computing and Machine Learning Infrastructure for Oregon Life Sciences, Elucidating the Structural Mechanism of NMDA Receptor Modulation by Cryo-Electron Microscopy, G6072362224, Pacific Northwest Center for Cryo-EM, Molecular mechanisms of exercise-induced synaptic plasticity in the hippocampus, G9000064187, 3D Structure and Function of Ligand-Gated Ion Channels
OpenAlex ID: W7124189190