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Glycine receptor autoantibodies and spinal disinhibition

甘氨酸受体自身抗体和脊髓去抑制

基本信息

批准号：
521064237
负责人：
Professorin Dr. Britta Qualmann
金额：
--
依托单位：
Institut für Klinische Neurobiologie
依托单位国家：
德国
项目类别：
Research Units
财政年份：
资助国家：
德国
起止时间：
项目状态：
未结题

来源：
https://gepris.dfg.de/gepris/projekt/521064237?language=en
关键词：
Glycine receptor autoantibodies spinal disinhibition

项目摘要

Glycine receptor (GlyR) autoantibodies are associated with stiff-person syndrome and the lifethreatening progressive encephalomyelitis with rigidity and myoclonus in children and adults. In the previous funding period, we uncovered that the autoantibodies are not only directed to postsynaptic GlyRs, but can also bind to presynaptic GlyRα subunits. Moreover, we found in some cases that autoantibodies target the postsynaptic GlyRβ subunit. Our recently established GlyR field evaluation at ultrastructural resolution by freeze-fracturing and immunogold labeling will be applied to reveal impairments of the nanoscale organization and plasticity of GlyRs in spinal cord neurons upon binding of distinct, characterized GlyR autoantibodies to postsynaptic GlyRs. We will unravel how intracellular adaptor and scaffolding proteins of the postsynaptic GlyR contribute to autoantibody effects on GlyR nanoscale organization and functionality. Autoantibody-induced mechanisms underlying dynamic changes of surface GlyRs will be investigated. Following our observation that GlyR autoantibodies additionally bind to presynaptic GlyRs we will determine the contribution of presynaptic defects upon autoantibody presence to disease pathology. With these strategies we expect to elaborate if and how GlyR autoantibodies influence synaptic morphology and plasticity and thus to identify mechanisms underlying GlyR autoantibody pathology.

甘氨酸受体（GlyR）自身抗体与僵人综合征和危及生命的进行性脑脊髓炎（伴强直和肌阵挛）有关。在之前的资助期间，我们发现自身抗体不仅针对突触后GlyR，而且还可以结合突触前GlyRα亚基。此外，我们发现在某些情况下，自身抗体靶向突触后GlyRβ亚基。我们最近建立的GlyR领域的评价在超微结构分辨率冷冻断裂和免疫金标记将被应用于揭示损伤的纳米级组织和可塑性的GlyR在脊髓神经元后，结合不同的，特征性的GlyR自身抗体突触后GlyR。我们将揭开如何突触后GlyR的细胞内适配器和支架蛋白有助于自身抗体对GlyR纳米级组织和功能的影响。将研究自身抗体诱导的表面GlyRs动态变化的机制。在我们观察到GlyR自身抗体另外结合突触前GlyR之后，我们将确定自身抗体存在时突触前缺陷对疾病病理学的贡献。通过这些策略，我们希望详细说明GlyR自身抗体是否以及如何影响突触形态和可塑性，从而确定GlyR自身抗体病理学的机制。