Lee Sin Yi, Shoji Hirotaka, Shimozawa Aki, Aoyagi Hirofumi, Sato Yoshiaki, Tsumagari Kazuya, Terumitsu Mika, Motegi Haruhiko, Okada Kensuke, Sekiguchi Koji, Kuromitsu Junro, Nakahara Jin, Miyakawa Tsuyoshi, Ito Daisuke
From the Department of Neurology (S.Y.L., H.M., K.O., K.S., J.N.), Keio University School of Medicine, Tokyo; Division of Systems Medical Science (H.S., T.M.), Center for Medical Science, Fujita Health University, Toyoake; Eisai-Keio Innovation Laboratory for Dementia (A.S., H.A., Y.S., M.T., J.K.), Human Biology Integration, DHBL, Eisai Co., Ltd., Shinjuku-ku; Proteome Homeostasis Research Unit (K.T.), RIKEN Center for Integrative Medical Sciences, Yokohama; Department of Neurology (H.M.), The Jikei University School of Medicine; and Department of Physiology/Memory Center (D.I.), Keio University School of Medicine, Tokyo, Japan.
Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200234. doi: 10.1212/NXI.0000000000200234. Epub 2024 Apr 24.
Anti-IgLON5 disease is an autoimmune neurodegenerative disorder characterized by various phenotypes, notably sleep and movement disorders and tau pathology. Although the disease is known to be associated with the neuronal cell adhesion protein IgLON5, the physiologic function of IgLON5 remains elusive. There are conflicting views on whether autoantibodies cause loss of function, activation of IgLON5, or inflammation-associated neuronal damage, ultimately leading to the disease. We generated IgLON5 knockout (-/-) mice to investigate the functions of IgLON5 and elucidate the pathomechanism of anti-IgLON5 disease.
IgLON5 knockout (-/-) mice underwent behavioral tests investigating motor function, psychiatric function (notably anxiety and depression), social and exploratory behaviors, spatial learning and memory, and sensory perception. Histologic analysis was conducted to investigate tau aggregation in mice with tauopathy.
IgLON5 mice had poorer performance in the wire hang and rotarod tests (which are tests for motor function) than wild-type mice. Moreover, IgLON5-/- mice exhibited decreased anxiety-like behavior and/or hyperactivity in behavior tests, including light/dark transition test and open field test. IgLON5-/- mice also exhibited poorer remote memory in the contextual fear conditioning test. However, neither sleeping disabilities assessed by EEG nor tau aggregation was detected in the knockout mice.
These results suggest that IgLON5 is associated with activity, anxiety, motor ability, and contextual fear memory. Comparing the various phenotypes of anti-IgLON5 disease, anti-IgLON5 disease might partially be associated with loss of function of IgLON5; however, other phenotypes, such as sleep disorders and tau aggregation, can be caused by gain of function of IgLON5 and/or neuronal damage due to inflammation. Further studies are needed to elucidate the role of IgLON5 in the pathogenesis of anti-IgLON5 diseases.
抗IgLON5疾病是一种自身免疫性神经退行性疾病，具有多种表型，尤其是睡眠和运动障碍以及tau病理改变。尽管已知该疾病与神经元细胞粘附蛋白IgLON5相关，但IgLON5的生理功能仍不清楚。关于自身抗体是导致功能丧失、IgLON5激活还是炎症相关的神经元损伤，最终导致该疾病，存在相互矛盾的观点。我们制备了IgLON5基因敲除（-/-）小鼠，以研究IgLON5的功能并阐明抗IgLON5疾病的发病机制。
对IgLON5基因敲除（-/-）小鼠进行行为测试，以研究运动功能、精神功能（尤其是焦虑和抑郁）、社交和探索行为、空间学习和记忆以及感觉知觉。进行组织学分析以研究患有tau病变的小鼠中的tau聚集情况。
IgLON5基因敲除小鼠在悬尾试验和转棒试验（运动功能测试）中的表现比野生型小鼠差。此外，IgLON5-/-小鼠在行为测试（包括明暗转换试验和旷场试验）中表现出焦虑样行为减少和/或多动。IgLON5-/-小鼠在情境恐惧条件反射试验中的远期记忆也较差。然而，在基因敲除小鼠中未检测到通过脑电图评估的睡眠障碍和tau聚集。
这些结果表明IgLON5与活动、焦虑、运动能力和情境恐惧记忆有关。比较抗IgLON5疾病的各种表型，抗IgLON5疾病可能部分与IgLON5功能丧失有关；然而，其他表型，如睡眠障碍和tau聚集，可能由IgLON5功能获得和/或炎症引起的神经元损伤导致。需要进一步研究以阐明IgLON5在抗IgLON5疾病发病机制中的作用。
