Structural and functional mechanisms of anti-NMDAR autoimmune encephalitis

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dc.contributor.authorMichalski, Kevin
dc.contributor.authorAbdulla, Taha
dc.contributor.authorKleeman, Sam
dc.contributor.authorSchmidl, Lars
dc.contributor.authorGómez García, Ricardo
dc.contributor.authorSimorowski, Noriko
dc.contributor.authorVallese, Francesca
dc.contributor.authorPrüss, Harald
dc.contributor.authorHeckmann, Manfred
dc.contributor.authorGeis, Christian
dc.contributor.authorFurukawa, Hiro
dc.date.accessioned2024-09-10T10:32:32Z
dc.date.available2024-09-10T10:32:32Z
dc.date.issued2024-09-03
dc.description.abstractAutoantibodies 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.
dc.description.departmentDepto. de Farmacología y Toxicología
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.statuspub
dc.identifier.citationMichalski, K., Abdulla, T., Kleeman, S. et al. Structural and functional mechanisms of anti-NMDAR autoimmune encephalitis. Nat Struct Mol Biol (2024). https://doi.org/10.1038/s41594-024-01386-4
dc.identifier.doi10.1038/s41594-024-01386-4
dc.identifier.essn1545-9985
dc.identifier.issn1545-9993
dc.identifier.officialurlhttps://doi.org/10.1038/s41594-024-01386-4
dc.identifier.relatedurlhttps://www.nature.com/articles/s41594-024-01386-4
dc.identifier.urihttps://hdl.handle.net/20.500.14352/108052
dc.journal.titleNature Structural and Molecular Biology
dc.language.isoeng
dc.publisherSpringer Nature
dc.rights.accessRightsrestricted access
dc.subject.cdu616.831-002
dc.subject.ucmBioquímica (Medicina)
dc.subject.ucmBiología molecular (Biología)
dc.subject.ucmNeurociencias (Medicina)
dc.subject.unesco3207.11 Neuropatología
dc.titleStructural and functional mechanisms of anti-NMDAR autoimmune encephalitis
dc.typejournal article
dc.type.hasVersionVoR
dspace.entity.typePublication
relation.isAuthorOfPublicationdf79fd2c-2e90-44d0-b3ac-76ff241e2fc5
relation.isAuthorOfPublication.latestForDiscoverydf79fd2c-2e90-44d0-b3ac-76ff241e2fc5
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