The LGI1 protein: molecular structure, physiological functions and disruption-related seizures

Abstract

Leucine-rich, glioma inactivated 1 (LGI1) is a secreted glycoprotein, mainly expressed in the brain, and involved in central nervous system development and physiology. Mutations of LGI1 have been linked to autosomal dominant lateral temporal lobe epilepsy (ADLTE). Recently auto-antibodies against LGI1 have been described as the basis for an autoimmune encephalitis, associated with specific motor and limbic epileptic seizures. It is the second most common cause of autoimmune encephalitis. This review presents details on the molecular structure, expression and physiological functions of LGI1, and examines how their disruption underlies human pathologies. Knock-down of LGI1 in rodents reveals that this protein is necessary for normal brain development. In mature brains, LGI1 is associated with Kv1 channels and AMPA receptors, via domain-specific interaction with membrane anchoring proteins and contributes to regulation of the expression and function of these channels. Loss of function, due to mutations or autoantibodies, of this key protein in the control of neuronal activity is a common feature in the genesis of epileptic seizures in ADLTE and anti-LGI1 autoimmune encephalitis.

Keywords: AMPA receptors; Autoimmune encephalitis; Genetic epilepsy; Kv1; LGI1.

Figure 1

Domain organization of LGI1 and localization of mutations linked to ADLTE. Mutations are distributed along the whole gene sequence, without domain-preference. The list of mutations was compiled from Boillot and Baulac, 2016 [95] and Yamagata and Fukai, 2020 [96]. SP: signal peptide (cleaved in mature protein); C: cysteine cluster

Figure 2

Synaptic organization of LGI1 and disruption by mutations and autoantibodies. A Organization of LGI1 in a trans-synaptic complex with protein partners, and indirect functional interactions with presynaptic Kv1 channels and postsynaptic AMPA-Rs. B Pathogenic disruptions of LGI1, either by loss-of-function mutation or by autoantibodies. LGI1 alterations were shown to disrupt both Kv1 channels and AMPA-R expression and function. This could result from (1) internalization of Kv1 channels with their protein complex [133], (2) a decrease in Kv1 current, through fast-inactivation mediated by Kvβ1 [65, 86], (3) removal of Kv1 channels and AMPA-R from the synapse, or decreased expression [45, 85, 133, 138]. The loss of Kv1 currents enhances neurotransmitter release and so increases synaptic glutamate levels. Similarly, internalization, loss of channel function or changes in synaptic expression might be involved for AMPA-R channels. These may be the most promising candidate mechanisms that link LGI1 disruption to seizures. We used Servier Medical Art to create the figure

Figure  3

Two main targets of anti-LGI1 encephalitis: mesial temporal lobe and motor cortex. Left, Mesial temporal lobe involvement. Hippocampal hyper-intensity and edema can be found on the brain MRI (top left, coronal T2 image), as well as focal fronto-temporal lobe seizures (middle left; arrows indicate the EEG channels involved in the seizure) on EEG, and hippocampal hypermetabolism on F18–FDG–PET (bottom left; coronal view, superimposed on brain MRI). A striking bilateral striatal hypermetabolism is often detected in anti-LGI1 AE. Right, Motor cortex involvement. Tonic–dystonic seizures (TDS), also called faciobrachial dystonic seizures (FBDS), occur as in the top right (tonic contraction of the right hemiface and arm). Concomitant scalp EEG shows a fronto-central slow wave (middle right, black arrows) before the contralateral muscle contraction (white arrow, right arm EMG). F18–FDG–PET (bottom right) shows a hypermetabolism located on the primary motor cortex. EEG, MRI, and F18–FDG–PET figures are reproduced with permission from Navarro et al. 2016 [10]

Figure 4

Natural clinical history of anti-LGI1 encephalitis. At disease onset unilateral motor cortex (unilateral TDS, top left) or mesial temporal lobe (isolated mesial temporal lobe seizure, bottom left) may be equally affected structures. The further evolution is characterized by bilateral involvement, leading to either bilateral TDS, or cognitive disorders and MTLS. Finally, both structures, motor cortex and mesial temporal lobe, may be involved. The figure is reproduced with permission from Navarro et al. 2016 [10]