Structural and functional mechanisms of anti-NMDAR autoimmune encephalitis

Michalski, Kevin, Abdulla, Taha, Kleeman, Sam, Schmidl, Lars, Gómez, Ricardo, Simorowski, Noriko, Vallese, Francesca, Prüss, Harald, Heckmann, Manfred, Geis, Christian, Furukawa, Hiro (September 2024) Structural and functional mechanisms of anti-NMDAR autoimmune encephalitis. Nature Structural & Molecular Biology. ISSN 1545-9993 (Public Dataset)

URL: https://www.ncbi.nlm.nih.gov/pubmed/39227719

DOI: 10.1038/s41594-024-01386-4

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.

Item Type:	Paper
Subjects:	Investigative techniques and equipment > microscopy > Cryo-electron microscopy Investigative techniques and equipment Investigative techniques and equipment > microscopy
CSHL Authors:	Michalski, Kevin Kleeman, Sam Simorowski, Noriko Furukawa, Hiro Gomez, Ricardo
Communities:	CSHL labs > Furukawa lab CSHL labs > Janowitz lab School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	3 September 2024
Date Deposited:	04 Sep 2024 13:51
Last Modified:	10 Dec 2024 15:12
Related URLs:	Publisher
Dataset ID:	EMDB: 43544 EMDB: 43559 EMDB: 43531 EMDB: 43532 EMDB: 43537 EMDB: 43530 EMDB: 43540 EMDB: 43541 EMDB: 43538 EMDB: 43534 EMDB: 43536 EMDB: 43539 PDB: 8VUY PDB: 8VVH PDB: 8VUJ PDB: 8VUL PDB: 8VUR PDB: 8VUH PDB: 8VUU PDB: 8VUV PDB: 8VUS PDB: 8VUN PDB: 8VUQ PDB: 8VUT
URI:	https://repository.cshl.edu/id/eprint/41650

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