An Integrated Multi-Omic Network Analysis Identifies Seizure-Associated Dysregulated Pathways in the GAERS Model of Absence Epilepsy.

Absence epilepsy syndromes are part of the genetic generalized epilepsies, the pathogenesis of which remains poorly understood, although a polygenic architecture is presumed. Current focus on single molecule or gene identification to elucidate epileptogenic drivers is unable to fully capture the complex dysfunctional interactions occurring at a genetic/proteomic/metabolomic level. Here, we employ a multi-omic, network-based approach to characterize the molecular signature associated with absence epilepsy-like phenotype seen in a well validated rat model of genetic generalized epilepsy with absence seizures. Electroencephalographic and behavioral data was collected from Genetic Absence Epilepsy Rats from Strasbourg (GAERS, n = 6) and non-epileptic controls (NEC, n = 6), followed by proteomic and metabolomic profiling of the cortical and thalamic tissue of rats from both groups. The general framework of weighted correlation network analysis (WGCNA) was used to identify groups of highly correlated proteins and metabolites, which were then functionally annotated through joint pathway enrichment analysis. In both brain regions a large protein-metabolite module was found to be highly associated with the GAERS strain, absence seizures and associated anxiety and depressive-like phenotype. Quantitative pathway analysis indicated enrichment in oxidative pathways and a downregulation of the lysine degradation pathway in both brain regions. GSTM1 and ALDH2 were identified as central regulatory hubs of the seizure-associated module in the somatosensory cortex and thalamus, respectively. These enzymes are involved in lysine degradation and play important roles in maintaining oxidative balance. We conclude that the dysregulated pathways identified in the seizure-associated module may be involved in the aetiology and maintenance of absence seizure activity. This dysregulated activity could potentially be modulated by targeting one or both central regulatory hubs.

Multi-omics integration and epilepsy: Towards a better understanding of biological mechanisms.

The epilepsies are a group of complex neurological disorders characterised by recurrent seizures. Approximately 30% of patients fail to respond to anti-seizure medications, despite the recent introduction of many new drugs. The molecular processes underlying epilepsy development are not well understood and this knowledge gap impedes efforts to identify effective targets and develop novel therapies against epilepsy. Omics studies allow a comprehensive characterisation of a class of molecules. Omics-based biomarkers have led to clinically validated diagnostic and prognostic tests for personalised oncology, and more recently for non-cancer diseases. We believe that, in epilepsy, the full potential of multi-omics research is yet to be realised and we envisage that this review will serve as a guide to researchers planning to undertake omics-based mechanistic studies.