Project Details
Projekt
Autoantibodies and glycinergic dysfunction: Pathophysiology of associated motor disorders
Subject Area
Molecular and Cellular Neurology and Neuropathology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
from 2016 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 290514711
Disorders of the motor system associated with autoantibodies to glycine receptors (GlyRs) are RARE diseases such as stiff person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM). The reduction of inhibitory neurotransmission in these disorders is associated with neuromotor hyperexcitability. Although immunotherapy directed at reducing autoantibody levels may lead to improvement of patients symptoms, relapses are often observed. We need to understand the underlying pathomechanisms in the inhibitory synaptic network to improve therapy and to develop relapse prevention strategies. Currently, enhanced GlyR internalization has been described in the presence of autoantibodies, but the functional consequences are not known. The proposed research project will investigate the autoantibody related pathomechanisms at the inhibitory synapse, combining methodological aspects of neurobiology with autoimmune research and neurology. We have preliminary evidence that autoantibodies interfere directly with GlyR function. Using a recombinant cell cuture system, we could demonstrate that autoantibody-binding leads to decreased functionality of the ion channel GlyRalpha1. Most autoantibodies specifically recognize native epitopes in the large N-terminal extracellular domain. Based on these experiments we plan to investigate the action of autoantibodies at the targeted receptor. This proposal will investigate the following main points: (1) in vitro characterization of autoantibodies using transfected cell lines and murine primary neurons with regard to specificity, epitope mapping and importance for ligand-binding (2) influence of autoantibodies on receptor functionality using physiological readouts (3) receptor stability in in vitro internalisation assays, (4) in vivo action of autoantibodies in an animal model following passive transfer, (5) peptide neutralization as therapeutical option.
DFG Programme
Research Grants
