Epilepsy Proteome Pinpoints GNB1 Pathways, Other New Treatment Targets for Epilepsy

By Marilynn Larkin

March 22, 2021

NEW YORK (Reuters Health) - An analysis of brain samples from epilepsy patients and controls revealed differences in expression of hundreds of proteins in the hippocampus and other brain regions, and identified G-protein Subunit Beta 1 (GNB1) as a promising treatment target.

"Currently, no FDA-approved anti-seizure drug suppresses epileptic seizures by directly acting on G-protein-coupled receptors (GPCRs),". Dr. Thomas Wisniewski of New York University School of Medicine in New York City told Reuters Health by email. "GNB1 is involved in 28 pathways that are significantly impacted in the hippocampus of epilepsy cases, and 15 of these pathways include GPCRs with an FDA-approved drug for non-epilepsy-related indications."

"Hence," he said, "our data suggest that some currently FDA approved medications may have benefits as novel anti-epileptic drugs (AEDs)."

As reported in Brain Communications, Dr. Wisniewski and colleagues used mass spectrometry to study the hippocampal Cornu Ammonis 1-3 region (CA1-3), frontal cortex, and dentate gyrus microdissected from a total of 14 brain samples from individuals with epilepsy and controls.

Among the findings, according to Dr. Wisniewski:

- Of the 939 significantly altered proteins in both the hippocampus and frontal cortex, 20 were encoded by genes in which mutations cause epilepsy.

- 98/939 proteins (10.4%) were encoded by neurodevelopment-associated epilepsy genes, epilepsy-related genes, or potentially epilepsy-associated genes. "This finding validated the approach we are using," he said.

- 696/939 (74%) significant proteins had similar directional changes in both the hippocampus and frontal cortex in epilepsy. "These findings suggest that most pathological protein changes in epilepsy occurred in both regions, but to a different degree," he explained, "supporting greater vulnerability or a primary role of the hippocampus compared to the frontal cortex."

- Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signaling, and synaptic plasticity were particularly altered in epilepsy.

- GNB1 was one of the most significantly decreased proteins in all regions studied, highlighting the importance of G-protein subunit signaling and GPCRs in epilepsy.

Dr. Wisnieweski said, "We are currently testing the anti-epileptic activity of some candidate drugs that target GPCRs, with the hope that these agents (or their derivatives) might prove to be novel AEDs.

Dr. Anto Bagic, Director, University of Pittsburgh Comprehensive Epilepsy Center in Pennsylvania, commented in an email to Reuters Health, "We commend the authors for their pioneering work...Yet, we shouldn't jump too far in our conclusions since much more research and understanding is necessary to contextualize these findings fully."

"We must remain cautious in making simplistic assumptions about and attributions to the causes of epilepsies (that are largely unknown even in 2021), consequences of seizures (that are multiple, diverse, and incompletely understood), effects of the long-term use of antiseizure medications (that are vastly unknown) and confounders such as other neurotropic medications and comorbidities," he said. "This novel proteomic sketch will have to be transformed into the detailed pathophysiologic landscape through many more studies to fully validate, explore and exploit these findings."

Dr. Aristea S Galanopoulou, a professor in the department of neuroscience and division of child neurology at Albert Einstein College of Medicine in New York City, also commented by email to Reuters Health, "The intriguing message of this study is that some of these proteomic changes may be common across subjects with different types of epilepsies."

That said, she added, "This is a small-scale study...Generalization of findings to each of the numerous epilepsy syndromes and types across the lifespan, including the very young or older and all genders, needs to be cautiously done and confirmed by future research studies."

"Similarly, this end-of-life study cannot address which of the changes are mechanistically linked to epilepsy development, rather than reflect disease progression, comorbidities or treatment effects. It is also unclear in this exploratory study which of the observed proteomic changes are clinically relevant or simply compensatory."

SOURCE: https://bit.ly/3109GR6 Brain Communications, online March 9, 2021.

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