Autoantibodies and glycinergic dysfunction: Pathophysiology of associated motor disorders

• Applicants: Professorin Dr. Claudia Sommer; Professorin Dr. Carmen Villmann
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 290514711

• Final Report Year: 2020

Final Report Abstract

The present project investigated the pathology of glycine receptor autoantibodies. Patients harboring glycine receptor autoantibodies suffer from stiff person syndrome or the more severe form progressive encephalomyelitis with rigidity and myoclonus - PERM. Our project used transfected cell lines to determine binding of autoantibodies from patient serum, patient CSF, and from purified IgG of plasmapheresis material to the glycine receptor. Transfected cells were further used to determine functional impairment of glycine receptors following preincubation with patient serum. Receptor affinity to the agonist glycine and the antagonist strychnine determined by radioligand binding assays was unaffected. Unaffected glycine efficacy but largely reduced glycine potency was exhibited by electrophysiological recordings. A reduction in glycine potency was identified for 6 different patient sera and purified IgG form 3 patients arguing for a general mechanism of glycinergic impairment in the presence of autoantibodies. The far N-terminal domain of the glycine receptor was mapped as a common epitope for glycine receptor autoantibody binding between residues A29 and G62. The zebrafish model was used to show the causal pathogenicity of glycine receptor autoantibodies. As a readout, the escape response of the zebrafish was used following a tactile stimulus. The escape response war impaired in the presence of patient autoantibodies. The disturbed escape response is compatible with an enhanced startle response as typically observed in stiff person syndrome patients or patients with PERM.

Publications

• Investigations into the pathogenic properties of glycine receptors using transfected human embryonic kidney cells and zebrafish embryos. Autoimmune Symposium, Israel 2016
  N. v. Wardenburg, K. Ogino, H. Hirata, C. Villmann
  
• Glycine receptor autoantibodies and their pathomechanism in Stiff person syndrome. Eureka Würzburg 10.-11. October 2018
  V. Roemer, N. v. Wardenburg, N. Schaefer, C. Sommer, and C. Villmann
  
• Glycine receptor autoantibodies in Stiff person syndrome lead to impaired receptor functionality, Bonn Brain Meeting, Synapses and Circuits, 27.-29.03.2018
  V. Roemer, N. v. Wardenburg, N. Schaefer, C. Sommer, and C. Villmann
  
• Impaired Glycine receptor trafficking in neurological diseases. Front Mol Neurosci. 2018 Aug 21;11:291
  Schaefer N, Roemer V, Janzen D, Villmann C
  (See online at https://doi.org/10.3389/fnmol.2018.00291)
• New insights into the pathology of glycine receptor autoantibodies in Stiff person syndrome, SFN Meeting, 48th Annual Meeting, San Diego, USA 2018
  V. Roemer, N. v. Wardenburg, N. Schaefer, E. Tüzün, C. Sommer, and C. Villmann
  
• Disrupted glycinergic inhibition in human patients harboring glycine receptor autoantibodies. Jacques Monod Conference “Ligand-gated ion channels from atomic structure to synaptic transmission, Roscoff, France, May 20-24, 2019
  V. Roemer, N. von Wardenburg, N. Schaefer, K. Ogino, H. Hirata, C. Sommer, and C. Villmann
  
• Glycine receptor autoantibodies impair receptor function and induce motor dysfunction. Ann Neurol. 2020
  Rauschenberger V, von Wardenburg N, Schaefer N, Ogino K, Hirata H, Lillesaar C, Kluck CJ, Meinck HM, Borrmann M, Weishaupt A, Doppler K, Wickel J, Geis C, Sommer C, Villmann C
  (See online at https://doi.org/10.1002/ana.25832)