Epileptic Phenotypes Associated With SNAREs and Related Synaptic Vesicle Exocytosis Machinery.

Elisa Cali,Vincenzo Salpietro,Henry Houlden,Clarissa Rocca

doi:10.3389/fneur.2021.806506

Abstract

SNAREs (soluble N-ethylmaleimide sensitive factor attachment protein receptor) are an heterogeneous family of proteins that, together with their key regulators, are implicated in synaptic vesicle exocytosis and synaptic transmission. SNAREs represent the core component of this protein complex. Although the specific mechanisms of the SNARE machinery is still not completely uncovered, studies in recent years have provided a clearer understanding of the interactions regulating the essential fusion machinery for neurotransmitter release. Mutations in genes encoding SNARE proteins or SNARE complex associated proteins have been associated with a variable spectrum of neurological conditions that have been recently defined as “SNAREopathies.” These include neurodevelopmental disorder, autism spectrum disorder (ASD), movement disorders, seizures and epileptiform abnormalities. The SNARE phenotypic spectrum associated with seizures ranges from simple febrile seizures and infantile spasms, to severe early-onset epileptic encephalopathies. Our study aims to review and delineate the epileptic phenotypes associated with dysregulation of synaptic vesicle exocytosis and transmission, focusing on the main proteins of the SNARE core complex (STX1B, VAMP2, SNAP25), tethering complex (STXBP1), and related downstream regulators.

Highlights

Epilepsy is defined as a large heterogeneous group of diseases in which individuals have an enduring predisposition to seizures [1], characterized by many different seizure types and epilepsy syndromes [2, 3].The term “epileptic encephalopathy” refers to a group of disorders in which unremitting epileptic activity contributes to progressive cerebral dysfunction [4]
We focused on the association between the SNARE complex and seizures
Deficits in the subunits of the core complex, Munc18-1 and complexin-1 are mainly associated with an overlapping spectrum of developmental delay, intellectual disability, epilepsy, and movement disorders

Summary

Introduction

Epilepsy is defined as a large heterogeneous group of diseases in which individuals have an enduring predisposition to seizures [1], characterized by many different seizure types and epilepsy syndromes [2, 3].The term “epileptic encephalopathy” refers to a group of disorders in which unremitting epileptic activity contributes to progressive cerebral dysfunction [4]. Pathogenic biallelic and monoallelic variants disrupting proteins of the SNARE complex and associated regulators are a known cause for neurodevelopmental disorders consisting of an overlapping phenotype of developmental delay (DD), intellectual disability (ID), movement disorders, and epilepsy. The SNARE phenotypic spectrum associated with seizures ranges from simple febrile seizures and infantile spasms, to severe early-onset epileptic encephalopathies. We review the epileptic phenotypes associated with dysregulation of synaptic vesicle exocytosis and transmission, focusing on the main proteins of the SNARE core complex (STX1B, VAMP2, SNAP25), assembly complex (STXBP1, UNC13A), and related downstream regulators.

Results

Conclusion