Autoantibodies against leucine-rich glioma-inactivated 1 occur in patients with encephalitis who present with frequent focal seizures and a pattern of amnesia consistent with focal hippocampal damage. To investigate whether the cellular and subcellular distribution of LGI1 may explain the localisation of these features, and hence gain broader insights into LGI1’s neurobiology, we analysed the detailed localisation of LGI1, and the diversity of its protein interactome, in mouse brains using patients-derived recombinant monoclonal LGI1-antibodies. Combined immunofluorescence and mass spectrometry analyses showed that LGI1 is enriched in excitatory and inhibitory synaptic contact sites, most densely within CA3 regions of the hippocampus. LGI1 is secreted in both neuronal somatodendritic and axonal compartments, and occurs in oligodendrocytic, neuro-oligodendrocytic and astro-microglial protein complexes. Proteomic data support the presence of LGI1/Kv1/MAGUK complexes, but did not reveal LGI1 complexes with postsynaptic glutamate receptors. Our results extend our understanding of regional, cellular and subcellular LGI1 expression profiles and reveal novel LGI1-associated complexes, thus providing insights into the complex biology of LGI1 and its relationship to seizures and memory loss.

中文翻译：

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源自患者的抗体揭示了 LGI1 的亚细胞分布和异质相互作用组

针对富含亮氨酸的神经胶质瘤灭活 1 的自身抗体出现在脑炎患者中，这些患者表现为频繁的局灶性癫痫发作和与局灶性海马损伤一致的健忘症模式。为了研究 LGI1 的细胞和亚细胞分布是否可以解释这些特征的定位，从而更广泛地了解 LGI1 的神经生物学，我们使用患者来源的小鼠大脑分析了 LGI1 的详细定位及其蛋白质相互作用组的多样性重组单克隆 LGI1 抗体。联合免疫荧光和质谱分析表明，LGI1 富含兴奋性和抑制性突触接触位点，最密集的是海马体的 CA3 区域。LGI1 分泌在神经元体树突和轴突隔室中，并出现在少突胶质细胞中，神经少突胶质细胞和星形小胶质细胞蛋白复合物。蛋白质组学数据支持 LGI1/Kv1/MAGUK 复合物的存在，但没有揭示 LGI1 复合物与突触后谷氨酸受体。我们的结果扩展了我们对区域、细胞和亚细胞 LGI1 表达谱的理解，并揭示了新的 LGI1 相关复合物，从而提供了对 LGI1 复杂生物学及其与癫痫发作和记忆丧失的关系的见解。