P4 Impact of IgLON5 autoantibodies on cerebellar circuits and neuronal pathology in human patients and mouse models

抗IgLON 5疾病是一种新型的自身免疫性脑炎，与抗细胞粘附分子IgLON 5的抗体有关，其特征是步态障碍、睡眠异常和脑干功能障碍。尸检研究显示，一些患者的脑干和小脑中存在特殊的tau蛋白病，而另一些患者仅显示炎性浸润，并伴有IgG 1和4的可变沉积。抗IgLON 5相关症状的突触和神经元机制在很大程度上仍然未知。因此，我们建议对9名IgLON 5患者的尸检组织进行全面的神经病理学研究（6名患有/3名没有tau蛋白病），以研究炎症，其对神经元的影响以及与神经变性的有趣联系。接下来，我们将探讨不同IgG亚类对原代培养物中神经元健康的作用。为了深入了解神经元功能障碍的病理机制，我们将建立一种基于被动IgG 1或IgG 4脑室内转移的疾病小鼠模型，并表征抗IgLON 5的结合模式，从而导致行为缺陷，并通过双光子成像评估行为小鼠小脑皮质中的神经元结构和功能。

Anti-IgLON5 disease is a novel form of autoimmune encephalitis, associated with antibodies against the cell-adhesion molecule IgLON5 and characterized by gait impairment, sleep abnormality and brainstem dysfunction. Autopsy studies revealed a peculiar tauopathy in the brainstem and cerebellum in some patients, while others show inflammatory infiltrates only, with variable deposits of IgG1 and 4. The synaptic and neuronal mechanisms underlying the anti-IgLON5-associated symptoms remain largely unknown. We thus propose to conduct comprehensive neuropathological investigations of autopsy tissue of nine IgLON5 patients (six with/three without tauopathy), to study inflammation, its impact on neurons and the intriguing link to neurodegeneration. We will next probe the role of different IgG subclasses on neuronal health in primary cultures. To gain insight into the pathomechanisms governing neuronal dysfunction, we will establish a mouse model of disease based on passive IgG1 or IgG4 intracerebroventricular transfer and characterize the binding pattern of anti-IgLON5, resulting behavioral deficits and assess neuronal structure and function in the cerebellar cortex of behaving mice by means of two-photon imaging.