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Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

By Geoffrey Pires, Dominique Leitner, Eleanor Drummond, Evgeny Kanshin, Shruti Nayak, Manor Askenazi, Arline Faustin, Daniel Friedman, Ludovic Debure, Beatrix Ueberheide, Thomas Wisniewski, Orrin Devinsky

Posted 21 Jul 2020
bioRxiv DOI: 10.1101/2020.07.21.209163

Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioral disorders, and increased mortality from direct (e.g., Sudden Unexpected Death in Epilepsy [SUDEP], accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signaling networks associated with epilepsy, we examined the proteome of brain samples from epilepsy and control cases. Label free quantitative mass spectrometry (MS) was performed on the hippocampal CA1,CA2 and CA3 regions, frontal cortex, and dentate gyrus microdissected from epilepsy and control cases (n=14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1,CA2 and CA3 regions, 296 proteins in the frontal cortex, and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G protein signaling, and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G protein Subunit Beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G protein subunit signaling and G protein coupled receptors (GPCRs) in epilepsy. Our results provide insights into the molecular mechanisms underlying epilepsy, which may allow for novel targeted therapeutic strategies. ### Competing Interest Statement The authors have declared no competing interest.

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