Autoimmune antibody-induced neuronal hyperactivity triggers pathological Tau in IgLON5 disease

Askin, B.; Cordero Gomez, C.; Duong, S. L.-L.; Kilic, C.; Goihl, A.; Newman, A.; Wagner, J.; Thomas, V.; Lamberty, J.; Huebschmann, S.; Semenova, E.; Koertvelyessy, P.; Reinhold, D.; Kornau, H.-C.; Turko, P.; Neher, J. J.; Schmitz, D. G.; Rost, B. R.; Diez, L.; Pruess, H.; Wegmann, S.

doi:10.1101/2024.03.10.584272

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bioRxiv · 10.1101/2024.03.10.584272

Autoimmune antibody-induced neuronal hyperactivity triggers pathological Tau in IgLON5 disease

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Abstract

Anti-IgLON5 disease is an autoimmune disease, in which autoantibodies (AABs) against the neuronal cell surface protein IgLON5 lead to profound brain dysfunction and Tau pathology. How -IgLON5 AABs cause neuronal Tau protein pathology and neurodegeneration remains unclear. We find that patient-derived -IgLON5 AABs cluster IgLON5 proteins with other cell surface proteins, leading to neuronal hyperactivity that triggers pathological Tau missorting and phosphorylation, typically observed early in Tau-related neurodegenerative diseases. In wildtype mice, -IgLON5 AABs induce hippocampal Tau phosphorylation and neuroinflammatory responses. Our findings establish a causal link between the -IgLON5 AABs and Tau pathology in anti-IgLON5 disease patients, and highlight the role of neuronal hyperactivity as a disease-overarching driver of Tau pathology and provide a potential target for therapeutic intervention. Teaser-IgLON5 autoantibodies induce clustering of neuronal cell surface proteins, leading to acute neuronal hyperactivity and Tau missorting.

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Askin, B., Cordero Gomez, C., Duong, S. L.-L., Kilic, C., Goihl, A., Newman, A., Wagner, J., Thomas, V., Lamberty, J., Huebschmann, S., Semenova, E., Koertvelyessy, P., Reinhold, D., Kornau, H.-C., Turko, P., Neher, J. J., Schmitz, D. G., Rost, B. R., Diez, L., Pruess, H., Wegmann, S.. 2024-03-13. Autoimmune antibody-induced neuronal hyperactivity triggers pathological Tau in IgLON5 disease. https://doi.org/10.1101/2024.03.10.584272

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