TY  - JOUR
A1  - Rauschenberger, Vera
A1  - von Wardenburg, Niels
A1  - Schaefer, Natascha
A1  - Ogino, Kazutoyo
A1  - Hirata, Hiromi
A1  - Lillesaar, Christina
A1  - Kluck, Christoph J.
A1  - Meinck, Hans‐Michael
A1  - Borrmann, Marc
A1  - Weishaupt, Andreas
A1  - Doppler, Kathrin
A1  - Wickel, Jonathan
A1  - Geis, Christian
A1  - Sommer, Claudia
A1  - Villmann, Carmen
T1  - Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction
JF  - Annals of Neurology
N2  - 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.
KW  - glycine receptor autoantibodies
KW  - behavioral disorders
KW  - neurology
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216005
VL  - 88
IS  - 3
SP  - 544
EP  - 561
ER  -