Insight into molecular mechanisms across epilepsy etiologies could lead to novel therapies
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Researchers have identified “critical pathways” and “novel proteins” that may be considered potential drug targets for patients with epilepsy, according to findings published in bioRxiv.
“Proteomic studies of human epilepsy brain tissue have been limited. For such an important and common condition, this is rather surprising,” Thomas M. Wisniewski, MD, Gerald J. and Dorothy R. Friedman Professor at New York University Alzheimer’s Disease Center and professor of neurology, pathology and psychiatry at New York University Grossman School of Medicine, told Healio Neurology. “There have been numerous genomic, epigenetic and transcriptomic studies conducted; however, there is poor correlation between RNA expression and protein level, with proteins being the target of epilepsy drug treatments. A partial explanation is that we only recently developed our proteomic technique that permits obtaining high yield proteomic data using formalin fixed paraffin embedded human brain tissue, which is relatively abundant, as opposed to using frozen tissue, which is relatively scarce and more difficult to use.”
Wisniewski and colleagues sought to define alterations in molecular signaling networks associated with seizures in epilepsy with various etiologies by examining the proteome of brain samples from patients with epilepsy vs. otherwise healthy controls. They performed label-free quantitative mass spectrometry on the hippocampal Cornu Ammonis 1-3 region, frontal cortex and dentate gyrus microdissected from both cases and controls.
The researchers found that, of the 939 substantially altered proteins identified in the frontal cortex and hippocampus, 20 proteins were encoded by gene mutations that cause epilepsy and 98 proteins were encoded by neurodevelopment-associated epilepsy genes, epilepsy-related genes or potential epilepsy-associated genes.
Wisniewski described the results as “robust.”
“This finding validated the approach that we are using,” he said. “Importantly, our results also indicated that 74% of significant proteins had similar directional changes in both the hippocampus and the frontal cortex in epilepsy, which suggests that most pathological protein changes in epilepsy occurred in both regions but to a different degree. This supports greater vulnerability or a primary role of the hippocampus compared with the frontal cortex.”
Moreover, the results showed substantial alterations in epilepsy with proteins involved in protein synthesis, mitochondrial function, G-protein signaling and synaptic plasticity, Wisniewski added.
In particular, the researchers found that G-protein Subunit Beta 1 was significantly decreased in epilepsy across all regions examined, thus, indicating the significance of G-protein subunit signaling and G-protein-coupled receptors in epilepsy.
“We were surprised to see such a large number of robust differences. Our findings point to some known pathways involved in neurodevelopment and genes implicated in epilepsy, but also novel proteins that could inform new therapies,” Orrin Devinsky, MD, professor in the departments of neurology, neurosurgery and psychiatry at NYU Grossman School of Medicine, told Healio Neurology. “G-protein Subunit Beta 1 is a fascinating protein that is involved in how nerve cells talk to each other, but it was not known to be relevant to epilepsy. It could be a key protein as it 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 in epilepsy.”
Devinsky added that he and colleagues are planning additional research to examine the most promising proteins in animal models and to study small molecules that influence their function as well as how those molecules affect animals’ tendency to experience seizures.
“If we find out exactly what the changes in G-protein Subunit Beta 1 translate to in cell physiology, we may screen for compounds that up- or down-regulate this protein’s activity and how such compounds influence seizure control in animal models. That could lead to a human therapy.”
Wisniewski elaborated on this potential application.
“Currently, no FDA-approved anti-seizure drug suppresses epileptic seizures by directly acting on G-protein-coupled receptors. Approximately 134 currently available drugs target G-protein-coupled receptors,” he said. “There are several drugs targeting these receptors involved in pathways that were significantly impacted in our epilepsy data set. G-protein Subunit Beta 1 is involved in 28 pathways that are significantly impacted in the hippocampus of epilepsy cases and 15 of these pathways include G-protein-coupled receptors with an FDA-approved drug for non-epilepsy related indications.”
As a result, the data from this study demonstrate that certain FDA-approved medications could have a benefit as novel anti-epileptic drugs.
“We are currently testing the anti-epileptic activity of some of these candidate drugs that target G-protein-coupled receptors, with the hope that these agents or their derivatives might prove to be novel anti-epileptic drugs,” Wisniewski added.