Patient-derived antibodies reveal the subcellular distribution and heterogeneous interactome of LGI1

authors

• Ramirez-Franco Jorge
• Debreux Kévin
• Extremet Johanna
• Maulet Yves
• Belghazi Maya
• Villard Claude
• Sangiardi Marion
• Youssouf Fahamoe
• El Far Lara
• Lévêque Christian
• Debarnot Claire
• Marchot Pascale
• Paneva Sofija
• Debanne Dominique
• Russier Michael
• Seagar Michael
• Irani Sarosh
• El Far Oussama

keywords

• Leucine-rich glioma inactivated 1 LGI1
• Auto-antibodies
• Limbic encephalitis
• Autosomal-dominant lateral temporal lobe epilepsy ADLTE
• Kv1 channels

abstract

Autoantibodies against leucine-rich glioma-inactivated 1 occur in patients with encephalitis who present with frequent focal seizures and a pattern of amnesia consistent with focal hippocampal damage. To investigate whether the cellular and subcellular distribution of LGI1 may explain the localisation of these features, and hence gain broader insights into LGI1’s neurobiology, we analysed the detailed localisation of LGI1, and the diversity of its protein interactome, in mouse brains using patients-derived recombinant monoclonal LGI1-antibodies. Combined immunofluorescence and mass spectrometry analyses showed that LGI1 is enriched in excitatory and inhibitory synaptic contact sites, most densely within CA3 regions of the hippocampus. LGI1 is secreted in both neuronal somatodendritic and axonal compartments, and occurs in oligodendrocytic, neuro-oligodendrocytic and astro-microglial protein complexes. Proteomic data support the presence of LGI1/Kv1/MAGUK complexes, but did not reveal LGI1 complexes with postsynaptic glutamate receptors. Our results extend our understanding of regional, cellular and subcellular LGI1 expression profiles and reveal novel LGI1-associated complexes, thus providing insights into the complex biology of LGI1 and its relationship to seizures and memory loss.

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