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Structural and functional mechanisms of anti-NMDAR autoimmune encephalitis

Nature Structural & Molecular Biology volume 31, pages 1975–1986 (2024)Cite this article

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Abstract

Autoantibodies against neuronal membrane proteins can manifest in autoimmune encephalitis, inducing seizures, cognitive dysfunction and psychosis. Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is the most dominant autoimmune encephalitis; however, insights into how autoantibodies recognize and alter receptor functions remain limited. Here we determined structures of human and rat NMDARs bound to three distinct patient-derived antibodies using single-particle electron cryo-microscopy. These antibodies bind different regions within the amino-terminal domain of the GluN1 subunit. Through electrophysiology, we show that all three autoantibodies acutely and directly reduced NMDAR channel functions in primary neurons. Antibodies show different stoichiometry of binding and antibody–receptor complex formation, which in one antibody, 003-102, also results in reduced synaptic localization of NMDARs. These studies demonstrate mechanisms of diverse epitope recognition and direct channel regulation of anti-NMDAR autoantibodies underlying autoimmune encephalitis.

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Fig. 1: Cryo-EM structures of NMDARs in complex with Fab-003-102, Fab-007-168 and Fab-008-218.
Fig. 2: IgG-003-102 leads to NMDAR channel dysfunction in primary neurons.
Fig. 3: Different monoclonal NMDAR IgG antibodies, but not Fab fragments, reduce synaptic NMDAR current upon short incubation.
Fig. 4: IgG-003-102 and engineered long-linker 003-102 antibodies, but not IgG-007-168 and IgG-008-218, reduce NMDAR localization in neuronal synapses.
Fig. 5: Cryo-EM structures of GluN1a-2A NMDARs in complex with IgG-007-168 and IgG-008-218.
Fig. 6: Cryo-EM structures of GluN1a-2A NMDARs in complex with IgG-003-102 show distinct conformation.
Fig. 7: Various patterns of binding and functional effects are mediated by different anti-NMDAR autoimmune IgGs.

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Data availability

Cryo-EM maps and coordinates generated during this study for rat GluN1a-2B Fab 003-102, rat GluN1a-2B Fab 003-102 local, human GluN1a-2A Fab 003-102, human GluN1a-2A Fab 003-102 local, human GluN1a-2A IgG 003-102, human GluN1a-2A IgG 003-102 splayed, human GluN1a-2B Fab 007-168, human GluN1a-2A Fab 007-168 local, human GluN1a-2A IgG 007-168, human GluN1a-2A Fab 008-218, human GluN1a-2A Fab 008-218 local and human GluN1a-2A IgG 008-218 were deposited in the Electron Microscopy Data Bank (EMDB) with accession codes EMD-43544, EMD-43559, EMD-43531, EMD-43532, EMD-43537, EMD-43530, EMD-43540, EMD-43541, EMD-43538, EMD-43534, EMD-43536 and EMD-43539, and in the PDB with accession codes: 8VUY, 8VVH, 8VUJ, 8VUL, 8VUR, 8VUH, 8VUU, 8VUV, 8VUS, 8VUN, 8VUQ and 8VUT. Source data are provided with this paper.

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Acknowledgements

We thank D. Thomas and M. Wang for managing the cryo-EM facility and the computing facility at Cold Spring Harbor Laboratory, respectively. N. Simorowski, C. Sommer and C. Reißig are thanked for their technical support. We thank O. Clark for the access to a mass photometry device and H. Haselmann and M. Kempfer for assistance in electrophysiological recordings and dSTORM imaging, respectively. This work was supported by NIH NS11745 and 113632 (H.F.), MH085926 (H.F.), NIH F32MH121061 (K.M.), Austin’s purpose (H.F.), Robertson funds at Cold Spring Harbor Laboratory, Doug Fox Alzheimer’s fund, Heartfelt Wing Alzheimer’s fund and the Gertrude and Louis Feil Family Trust (H.F.) and the German Research Foundation (FOR3004; GE2519/8-1, GE2519/9-1 and GE2519/11-1 to C.G.) by the German Federal Ministry of Education and Research (01GM1908B and 01EW1901 to C.G.), and the Schilling Foundation (C.G.).

Author information

Author notes

  1. These authors contributed equally: Kevin Michalski, Taha Abdulla.

  2. These authors jointly supervised this work: Christian Geis, Hiro Furukawa.

Authors and Affiliations

  1. W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

    Kevin Michalski, Sam Kleeman, Ricardo Gómez, Noriko Simorowski & Hiro Furukawa

  2. Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany

    Taha Abdulla, Lars Schmidl & Christian Geis

  3. School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

    Sam Kleeman & Hiro Furukawa

  4. Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA

    Francesca Vallese

  5. Department of Neurology and Experimental Neurology, Charité–Universitätsmedizin Berlin, Berlin, Germany

    Harald Prüss

  6. Department of Neurophysiology, Institute of Physiology, University of Würzburg, Würzburg, Germany

    Manfred Heckmann

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Contributions

K.M., R.G., M.H., C.G. and H.F. initiated and designed the experiments. N.S. made the DNA constructs and baculoviruses. R.G. purified the linked scFv constructs. T.A. conducted electrophysiology on neurons. K.M. and S.K. assessed NMDAR–antibody interactions and conducted single-particle cryo-EM. L.S. performed dSTORM and NMDAR localization assays. K.M. engineered the binding-attenuated mutant and the Fv fragment probes. H.P. provided NMDAR IgG and sequence information. F.V. and K.M. conducted mass photometry. K.M., H.F., T.A. and C.G. wrote the paper.

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Correspondence to Hiro Furukawa.

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Nature Structural & Molecular Biology thanks Laurent Groc, Wei Lu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. Primary Handling Editor: Sara Osman, in collaboration with the Nature Structural & Molecular Biology team.

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Extended data

Extended Data Fig. 1 Single-particle cryo-EM data processing for Fab-bound NMDARs (related to Fig. 1).

Particle processing workflows for Fab-bound NMDAR cryo-EM data. WARP-processed micrographs were used for blob picking and initial processing. Final volumes were generated in CryoSPARC 3.2.0 after template picking and cleanup using heterogeneous refinement followed by non-uniform refinement. Representative micrographs (scale bar corresponds to 25 nm), 2D averages, and intermediate volumes are shown.

Extended Data Fig. 2 Single-particle cryo-EM data processing for Fab-bound NMDARs (related to Fig. 1).

Local resolution and Fourier shell correlation of the entire complex (right panels) and locally refined map (one GluN1-2 ATD dimer and one Fab; left panels) for rat GluN1a-2B NMDAR/Fab-003-102 (a), GluN1a-2A NMDAR/Fab-003-102 (b), human GluN1a-2B NMDAR/Fab-007-168 (c), and human GluN1a-2A NMDAR/Fab-008-218 (d).

Extended Data Fig. 3 Representative cryo-EM density at the Fab binding sites (related to Fig. 1).

Cryo-EM density (blue mesh) of local refinement around GluN1a-2 ATD and Fab for human GluN1a-2A NMDAR/Fab-003-102 (a), human GluN1a-2B NMDAR/Fab-007-168 (b), and human GluN1a-2A NMDAR/Fab-008-218 (c) at the GluN1a-Fab binding sites.

Extended Data Fig. 4 Characterization of NMDAR mediated synaptic currents and GluN1 expression on neuronal dendrites (related to Figs. 2 and 4).

a, Whole-cell patch-clamp recordings in primary neurons (current-clamp mode) in the presence of NBQX and picrotoxin showing TTX-sensitive spontaneous action potentials. b-c, NMDAR-mediated spontaneous postsynaptic currents (sEPSC in the presence of NBQX and picrotoxin) are induced upon action potential firing and can be blocked by TTX (b). Application of AP-5 completely abolishes action potential elicited sEPSCs, thus demonstrating NMDAR mediated synaptic EPSCs (c). d-e, Quantification of GluN1 non-synaptic expression on neuronal dendrites upon 24 h antibody incubation (d: ncontrol IgG = 11; n003-102 IgG = 16; n003-102 attenuated = 16; n2xFv-long = 15, n2xFv-short = 14 dendrites. e: ncontrol IgG = 9; n007-168 IgG = 9; n008-218 IgG = 9 dendrites; n represent dendrites from individual neurons). f, Binding assessment of 2xFv short (scFv with short 20 amino acid residue linker) and long (scFv with short 80 amino acid residue linker) for the 003-102 antibody by FSEC using tryptophan fluorescence (280/330 nm excitation/emission). Arrows point to the peak shift, representing interactions with GluN1a-2A NMDAR proteins (GluN1/2 A). Boxes represent the median, 25th, and 75th percentile values, and the whiskers represent the minimum and maximum values. Treatment groups in d and e were compared using the non-parametric Kruskal-Wallis test with Dunn’s multiple comparisons. n.s., not significant. P-values are provided in the figure panels.

Source data

Extended Data Fig. 5 Cell viability is unaffected by low and high concentrations of control IgG and IgG 003-102 (related to Figs. 2 and 4).

a, Representative images showing no influence of higher IgG 003-102 concertation (100 µg/mL) on cell viability. DAPI-positive cells representing all cells are shown in the left column; dead cells (stained positive with Live-or-dye) are shown in the middle column; the right column is merged images. b, Quantitative analysis shows no significant influence of control IgG and IgG 003-102 in 10 and 100 µg/ml concentration on cell viability (nNo Abs = 10, ncontrol 10 µg/mL = 10, n003-102 IgG 10 µg/mL = 10, ncontrol 100 µg/mL = 13, n003-102 IgG 100 µg/mL = 9). n represents individual neuron preparations. c-d, Quantitative analyses of synaptic NMDAR responses showed reduced sEPSC peak amplitude but not frequency at both low (10 µg/ml) and high (100 µg/mL) concentrations of patient-derived IgG 003-102 (ncontrol 10 µg/mL = 8, n003-102 IgG 10 µg/mL = 9, ncontrol 100 µg/mL = 4, n003-102 IgG 100 µg/mL = 5). e-f, Quantitative analyses of synaptic NMDAR responses upon incubation of Control IgG 100 µg/mL at various time points showing unchanged sEPSC peak amplitude and frequency (ncontrol 30 mins = 5, ncontrol 6h = 5, ncontrol 24h = 5). Boxes represent the median, 25th, and 75th percentile values, and the whiskers represent the minimum and maximum values. n in c to f represent individual neuron preparations. Treatment groups in b to f were compared using One-way ANOVA with Sidak’s multiple comparison Test. n.s., not significant. P-values are shown in the figure.

Source data

Extended Data Fig. 6 Single-particle cryo-EM data processing for IgG-bound GluN1a-2A NMDARs (related to Figs. 5 and 6).

Particle processing of IgG-bound GluN1a-2A NMDARs. WARP-processed micrographs were used for blob picking and initial processing. Final volumes were generated in CryoSPARC 3.2.0 after template picking and cleanup using heterogeneous refinement followed by non-uniform refinement. Representative micrographs (scale bar corresponds to 25 nm), 2D averages, and intermediate volumes are shown.

Extended Data Fig. 7 Single-particle cryo-EM data processing for IgG-bound NMDARs (related to Figs. 5 and 6).

Local resolution and Fourier shell correlation (left panels) and representative cryo-EM density at the binding sites (right) for GluN1a-2A NMDAR/IgG-007-168 (a), GluN1a-2A NMDAR/IgG-008-218 (b), and GluN1a-2A NMDAR/IgG-003-102 (c).

Extended Data Fig. 8 Mass photometry of GluN1a-2A NMDAR bound to IgG-003-102 (related to Fig. 6).

Samples of IgG-003-102, GluN1a-2A, and SEC-purified GluN1a-2A NMDAR complexed with IgG-003-102 were each diluted to 0.2 mg/mL and pipetted onto a glass coverslip for mass measurement using a mass photometer (Refeyn). Histograms represent the particle counts and particle mass of IgG and NMDAR alone (a) or complexed together (b).

Supplementary information

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Supplementary Video 1

Supplementary Video 1. IgG-induced conformational alteration of NMDARs. A structural comparison between GluN1a-2A NMDARs bound to Fab-008-218 versus IgG-008-218 and GluN1a-2A NMDARs bound to Fab-003-102 versus IgG-003-102 reveals robust conformational changes. In both cases, the GluN1a-2A ATD dimer interfaces undergo substantial shifts toward an allosterically inhibited state when bound by the IgGs. This indicates that these autoimmune antibodies function as allosteric inhibitors.

Source data

Source Data Figs. 2–4 and Extended Data Figs. 4 and 5

Statistical source data for Figs. 2–4 and Extended Data Figs. 4 and 5.

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Michalski, K., Abdulla, T., Kleeman, S. et al. Structural and functional mechanisms of anti-NMDAR autoimmune encephalitis. Nat Struct Mol Biol 31, 1975–1986 (2024). https://doi.org/10.1038/s41594-024-01386-4

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