Vera Rauschenberger1, Niels von Wardenburg1, Natascha Schaefer1, Kazutoyo Ogino2, Hiromi Hirata2, Christina Lillesaar3, Christoph J Kluck4, Hans-Michael Meinck5, Marc Borrmann6, Andreas Weishaupt7, Kathrin Doppler7, Jonathan Wickel8, Christian Geis8, Claudia Sommer7, Carmen Villmann1. 1. Institute for Clinical Neurobiology, University Hospital, Julius Maximilian University of Würzburg, Würzburg, Germany. 2. Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University, Tokyo, Japan. 3. Department of Child and Adolescent Psychiatry, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany. 4. Institute of Biochemistry, Emil Fischer Center, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany. 5. Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany. 6. Witten, Helios University Hospital Wuppertal, Department of Nephrology and Rheumatology, Witten/Herdecke University, Germany. 7. Department of Neurology, University Hospital Würzburg, Würzburg, Germany. 8. Section of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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 2 patients, a decreased fraction of desensitized receptors was observed, whereas 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. INTERPRETATION: 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, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonus patients. ANN NEUROL 2020;88:544-561.
OBJECTIVE: 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. METHODS: 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. RESULTS: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 2 patients, a decreased fraction of desensitized receptors was observed, whereas 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. INTERPRETATION: 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, because the transfer of humanglycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonuspatients. ANN NEUROL 2020;88:544-561.
Authors: Niels Hansen; Michael Lipp; Jonathan Vogelgsang; Ruth Vukovich; Tristan Zindler; Daniel Luedecke; Stefan Gingele; Berend Malchow; Helge Frieling; Simone Kühn; Johannes Denk; Jürgen Gallinat; Thomas Skripuletz; Nicole Moschny; Jens Fiehler; Christian Riedel; Klaus Wiedemann; Mike P Wattjes; Inga Zerr; Hermann Esselmann; Stefan Bleich; Jens Wiltfang; Alexandra Neyazi Journal: Brain Behav Immun Health Date: 2020-10-01
Authors: Victoria P San Martín; Anggelo Sazo; Elías Utreras; Gustavo Moraga-Cid; Gonzalo E Yévenes Journal: Front Mol Neurosci Date: 2022-03-23 Impact factor: 5.639