ZFIN ID: ZDB-PUB-200627-5
GlyR autoantibodies impair receptor function and induce motor dysfunction
Rauschenberger, V., Wardenburg, N.V., Schaefer, N., Ogino, K., Hirata, H., Lillesaar, C., Kluck, C.J., Meinck, H.M., Borrmann, M., Weishaupt, A., Doppler, K., Wickel, J., Geis, C., Sommer, C., Villmann, C.
Date: 2020
Source: Annals of neurology   88(3): 544-561 (Journal)
Registered Authors: Hirata, Hiromi
Keywords: autoantibodies, epitope mapping, escape behavior, glycine receptor, internalization, patch clamp
MeSH Terms:
  • Adult
  • Aged
  • Animals
  • Autoantibodies/immunology*
  • Autoantibodies/pharmacology
  • Autoantigens/immunology
  • Behavior, Animal/drug effects
  • Encephalomyelitis/immunology*
  • Encephalomyelitis/metabolism
  • Epitopes, B-Lymphocyte/immunology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Muscle Rigidity/immunology*
  • Muscle Rigidity/metabolism
  • Receptors, Glycine/immunology
  • Receptors, Glycine/metabolism*
  • Stiff-Person Syndrome/immunology*
  • Stiff-Person Syndrome/metabolism
  • Zebrafish
PubMed: 32588476 Full text @ Ann. Neurol.
Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff-person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood.
A cell-based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model.
Glycine receptor function as assessed by glycine dose-response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from two patients a decreased fraction of desensitized receptors was observed while closing of the ion channel remained fast. The glycine receptor N-terminal residues 29 A to 62 G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals.
Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, since the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in SPS or PERM patients. This article is protected by copyright. All rights reserved.