Bilge Askin, Cagla Kilic, César Cordero Gómez, Sophie Lan-Linh Duong, Alvaro Domingues-Baquero, Alexander Goihl, Karsten Nalbach, Joana Petushi, Pia Grundschöttel, Jessica Wagner, Valentine Thomas, Janne Lamberty, Emily Withers, Hanna Huber, Sabrina Huebschmann, Ekaterina Semenova, Paul Turko, Andrew G. Newman, Lisa Diez, Marc Beyer, Elena De Domenico, Peter Körtvelyessy, Dirk Reinhold, Anja Schneider, Jonas J. Neher, Thomas Ulas, Stefan F. Lichtenthaler, Benjamin R. Rost, Dietmar Schmitz, Harald Prüss, Susanne Wegmann
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 α-IgLON5 AABs cause neuronal Tau protein pathology and neurodegeneration remains unclear. We find that patient-derived α-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 wild-type mice, α-IgLON5 AABs induce hippocampal Tau phosphorylation and neuroinflammatory responses. Our findings establish a causal link between the α-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.