Refine
Has Fulltext
- yes (24)
Is part of the Bibliography
- yes (24)
Year of publication
- 2024 (24) (remove)
Document Type
- Journal article (24) (remove)
Language
- English (24) (remove)
Keywords
- cell biology (2)
- hydrocarbons (2)
- ATF4 (1)
- C.376A>G (p.S126G) (1)
- Covid-19 (1)
- DCM genetic background (1)
- DNA double-strand breaks (1)
- DNA-encoded library synthesis (1)
- DNA-tagged amines (1)
- Drosophila (1)
Institute
- Neurologische Klinik und Poliklinik (5)
- Institut für Organische Chemie (4)
- Theodor-Boveri-Institut für Biowissenschaften (3)
- Comprehensive Cancer Center Mainfranken (2)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (2)
- Institut für Klinische Biochemie und Pathobiochemie (2)
- Institut für Pharmakologie und Toxikologie (2)
- Institut für Pharmazie und Lebensmittelchemie (2)
- Institut für Psychologie (2)
- Klinik und Poliklinik für Anästhesiologie (ab 2004) (2)
Sonstige beteiligte Institutionen
Glycine receptor β–targeting autoantibodies contribute to the pathology of autoimmune diseases
(2024)
Background and Objectives
Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα subunit–binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyRβ subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRβ making it not unlikely that GlyRβ-specific autoantibody (aAb) exist and contribute to the disease pathology.
Methods
In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRβ. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRβ binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyRβ aAb binding were resolved by whole-cell patch-clamp recordings.
Results
Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRβ aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRβ colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRβ aAb from both patients to its target impair glycine efficacy.
Discussion
Our study establishes GlyRβ as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRβ impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRβ aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.
In DNA-encoded library synthesis, amine-substituted building blocks are prevalent. We explored isocyanide multicomponent reactions to diversify DNA-tagged amines and reported the Ugi-azide reaction with high yields and a good substrate scope. In addition, the Ugi-aza-Wittig reaction and the Ugi-4-center-3-component reaction, which used bifunctional carboxylic acids to provide lactams, were explored. Five-, six-, and seven-membered lactams were synthesized from solid support-coupled DNA-tagged amines and bifunctional building blocks, providing access to structurally diverse scaffolds.