The role of LGI proteins in raising neuronal excitability and in epileptogenesis

Abstract

Introduction. Acording to WHO approximately 50 million people worldwide have epilepsy, making it one of the most common neurological diseases globally, and about two thirds of them are idiopatic. Certain types of idiopathic epilepsy are developed with the involvement of LGI family proteins. The role of LGI proteins (leucine-rich, glioma-inactivated protein-1) is to regulate synaptic transmission, activity of voltage-gated potassium channel (Kv1.1), and to inhibit neuroblastomas. The goal of this study is to highlight the role of LGI proteins in raising neuronal excitability and epileptogenesis.

Materials and methods. 12 articles from relevant scientific journals, as Nature Medicine, SAGE Journals, Journal of Neuroscience, have been studied.

Results. Two basic mechanisms are known by which LGI protein is involved in the development of neurological disorders: temporal lobe epilepsy (TLE) caused by mutation in LGI gene, and limbic encefalopathy (LE) caused by presence of antibodies anti-LGI. At the presynaptic membrane, truncated LGI1 fails to prevent rapid inactivation of the Kv1.1 potassium channel. The consequent high influx of Ca2+ triggers massive transmitter release of glutamate. Truncated LGI1 also fails to be secreted and does not bind ADAM22 (a disintegrin and metalloprotease domain) and other postsynaptic receptors. The augmented Src kinase activity maintains an immature NMDA receptor composition with high NR2B/NR2A ratio. As a consequence, NMDA receptor– mediated calcium currents last longer and enhance excitatory responses. Interaction between LGI1 and ADAM23 leads to decrease of seizure threshold, and interaction with ADAM22 recduce decrease expresion of AMPAreceptors. LGI1 antibodies Associated with LE neutralize the specific protein-protein interaction between LGI1 and ADAM22/ADAM23, inducing epileptogenetic effect.

Conclusion.Mutation of LGI1 gene, disruption of interaction between LGI proteins and ADAM proteins, ADAM proteins defects, lead to TLE phenotype, manifested by seizure, halucination, auditive disorders, memory disorders. At the same time the presence of antibodies anti-LGI or anti-NMDA leadt to LE, manifesting by lose of memory, iritability, headache, seizures and psychosis.

Key words: LGI, epilepsy, mutation.