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Title: | An Integrated Multi-Omic Network Analysis Identifies Seizure-Associated Dysregulated Pathways in the GAERS Model of Absence Epilepsy. | Austin Authors: | Harutyunyan, Anna;Chong, Debbie;Li, Rui;Shah, Anup D;Ali, Zahra;Huang, Cheng;Barlow, Christopher K;Perucca, Piero ;O'Brien, Terence J;Jones, Nigel C;Schittenhelm, Ralf B;Anderson, Alison;Casillas-Espinosa, Pablo M | Affiliation: | Epilepsy Research Centre Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC 3052, Australia.. Department of Neurology, Alfred Health, Melbourne, VIC 3004, Australia.. Monash Biomedical Proteomics Facility and Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.. Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.. Comprehensive Epilepsy Program Neurology |
Issue Date: | 28-May-2022 | Date: | 2022 | Publication information: | International journal of molecular sciences 2022; 23(11): 6063 | Abstract: | 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. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/30395 | DOI: | 10.3390/ijms23116063 | ORCID: | 0000-0002-6165-5639 0000-0001-9309-2829 0000-0002-1080-8439 0000-0001-8738-1878 0000-0002-7855-7066 |
Journal: | International journal of molecular sciences | PubMed URL: | 35682742 | PubMed URL: | https://pubmed.ncbi.nlm.nih.gov/35682742/ | Type: | Journal Article | Subjects: | ALDH2 GAERS GSTM1 WGCNA absence epilepsy lysine degradation metabolomics proteomics |
Appears in Collections: | Journal articles |
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