Patients' IgLON5 autoantibodies interfere with IgLON5-protein interactions.

Background

Anti-IgLON5 disease is a rare neurological disorder characterized by autoantibodies against IgLON5, and pathological evidence of neurodegeneration. IgLON5 is a cell adhesion molecule but its physiological function is unknown. Our aim was to investigate the IgLON5 interactome and to determine if IgLON5 antibodies (IgLON5-abs) affect these protein interactions.

Methods

IgLON5 interactome was investigated by mass spectrometry sequencing of proteins immunoprecipitated by IgLON5 autoantibodies using cultures of rat cerebellar granular neurons (CGNs). Shedding of IgLON5 was explored using HEK cells transfected with human IgLON5 plasmid and in CGNs. Interactions of IgLON5 with identified binding partners and IgLON5-abs effects were confirmed by immunofluorescence in transfected HEK cells and rat hippocampal neurons.

Results

Patients' IgLON5 antibodies co-precipitated all members of the IgLON family and three 3 additional surface proteins. IgLON5 predominantly establishes homomeric and heteromeric

Conclusions

We show a potentially novel pathogenic mechanism of IgLON5-abs that consists in blocking IgLON5 interactions with its binding partners. These findings extend our knowledge about the physiological role of IgLON5 and pave the way to future understanding of the pathological mechanisms of anti-IgLON5 disease.

Informations de copyright

Copyright © 2023 Landa, Serafim, Gaig, Saiz, Koneczny, Hoftberger, Santamaria, Dalmau, Graus and Sabater.

Déclaration de conflit d'intérêts

FG: royalties, Euroimmun for the use of IgLON5 as an autoantibody test. JD: royalties, Athena Diagnostic for use of Ma2 as an autoantibody test; royalties and Euroimmun for use of NMDA receptor, GABAB receptor, GABAA receptor, DPPX, and IgLON5 as autoantibody tests. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.