美国德克萨斯大学Ryan E. Hibbs、德国神经退行性疾病中心Harald Prüss等研究人员合作揭示GABAA受体自身免疫性脑炎的结构机制。相关论文于2022年7月7日发表在《细胞》杂志上。
研究人员确定了来自一个脑炎患者的与γ-氨基丁酸A型（GABAA）受体结合的抗体的冷冻电镜结构。这些抗体通过直接抑制GABAA功能诱发了严重的脑炎，导致神经系统过度兴奋。这些结构揭示了GABAA的抑制和病理机制。一种抗体直接与神经递质竞争，将受体锁定在类似静止的状态。第二个抗体针对的是参与结合苯二氮卓类药物的亚单位界面，并拮抗安定的增效作用。研究人员确定了这些抗体中涉及特异性和亲和力的关键残基，并利用电生理学证实了基于结构的功能效应假说。这些研究共同定义了人类患者自身免疫性脑炎的神经传递直接功能拮抗的机制。
据悉，针对神经元膜蛋白的自身抗体可以引起脑炎、癫痫发作和严重的行为异常。虽然已经确定了几个神经元靶点的抗体，但关于它们如何调节功能的结构细节还不清楚。
附：英文原文
Title: Structural mechanisms of GABAA receptor autoimmune encephalitis
Author: Colleen M. Noviello, Jakob Kreye, Jinfeng Teng, Harald Prüss, Ryan E. Hibbs
Issue&Volume: 2022/07/07
Abstract: Autoantibodies targeting neuronal membrane proteins can cause encephalitis, seizures,and severe behavioral abnormalities. While antibodies for several neuronal targetshave been identified, structural details on how they regulate function are unknown.Here we determined cryo-electron microscopy structures of antibodies derived froman encephalitis patient bound to the γ-aminobutyric acid type A (GABAA) receptor. These antibodies induced severe encephalitis by directly inhibiting GABAA function, resulting in nervous-system hyperexcitability. The structures reveal mechanismsof GABAA inhibition and pathology. One antibody directly competes with a neurotransmitterand locks the receptor in a resting-like state. The second antibody targets the subunitinterface involved in binding benzodiazepines and antagonizes diazepam potentiation.We identify key residues in these antibodies involved in specificity and affinityand confirm structure-based hypotheses for functional effects using electrophysiology.Together these studies define mechanisms of direct functional antagonism of neurotransmissionunderlying autoimmune encephalitis in a human patient.
DOI: 10.1016/j.cell.2022.06.025
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00730-9