LGI1 antibody induced pathophysiology at axon initial segments and presynaptic nerve terminals

具有针对“富含亮氨酸的神经胶质瘤灭活 1”（LGI1）蛋白的自身抗体的边缘脑炎是第二常见的自身免疫性脑炎亚型。 LGI1 的功能仍然知之甚少，但有证据表明 LGI1 由神经元分泌，形成跨突触二聚体，并控制轴突起始段 (AIS) 的功能。在第一个资助期间，我们发现致病性LGI1抗体会导致细胞兴奋性和突触释放概率增加。后者是由突触前钾通道 Kv1.1 和 Kv1.2 密度降低引起的，从而导致突触前动作电位增宽。为了揭示其潜在机制，我们将研究AIS处LGI1蛋白复合物的组成和功能，以及LGI1蛋白复合物在建立跨突触纳米柱中的作用。为此，我们将与墨卡托研究员 Masaki Fukata 教授（日本冈崎）合作，将冷冻断裂复制标记（R. Shigemoto）、超分辨率和扩展显微镜（M. Sauer）、AIS（S. Hallermann）的膜片钳记录以及 LGI1 的分子生物学结合起来，Masaki Fukata 教授是 LGI1 蛋白质复合物分子组成方面的著名专家。这些结果将增进我们对 LGI1 蛋白多重作用的理解，并阐明自身抗体诱导的病理机制。

Limbic encephalitis with autoantibodies against the protein “leucine-rich glioma inactivated 1” (LGI1) is the second most common subtype of autoimmune encephalitis. The function of LGI1 remains poorly understood but there is evidence that LGI1 is secreted by neurons, forms trans- synaptic dimers, and controls the function of the axon initial segment (AIS). In the first funding period, we found that pathogenic LGI1 antibodies cause an increase in cellular excitability and synaptic release probability. The latter is caused by a reduction in the density of the presynaptic potassium channels Kv1.1 and Kv1.2, which causes broadening of presynaptic action potential. To uncover the underlying mechanisms, we will study the composition and function of the LGI1 protein complex at the AIS and the role of the LGI1 protein complex for the establishment of trans- synaptic nano-columns. To this end, we will combine freeze-fracture replica labeling (R. Shigemoto), super-resolution and expansion microscopy (M. Sauer), and patch-clamp recordings from the AIS (S. Hallermann) as well as the molecular biology of LGI1 in collaboration with the Mercator fellow Prof. Masaki Fukata (Okazaki, Japan), who is a renowned expert on the molecular composition of the LGI1 protein complex. These results will improve our understanding of the multiple roles of the LGI1 protein and will elucidate autoantibody-induced pathomechanisms.