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Epilepsy: From Molecular Basis to Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 31 July 2024 | Viewed by 4324

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Special Issue Editor

Dr. Henry Hing Cheong Lee

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Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA 02115, USA
Interests: epilepsy

Special Issue Information

Dear Colleagues,

Epilepsy is a generalizable neuropathology arising from a wide range of etiologies, including genetic malfunctions, metabolic disorders, and brain trauma. Regardless of the underlying cause, an imbalance between excitatory and inhibitory neurotransmission is often associated with epilepsy. A better understanding of the molecular mechanisms governing proper excitatory and inhibitory neurotransmission is therefore important for identifying relevant therapeutic targets. In this Special Issue, we aim to cover the latest research on the molecular mechanisms underlying epileptogenesis, as well as rational therapeutic design based on our latest knowledge. We will focus specifically on three areas of research: (1) ion channels or transporters that underlie excitatory and inhibitory neurotransmissions, (2) reversibility of excitatory and inhibitory neurotransmissions during epileptogenesis, and (3) epilepsy models that allow systematic investigations of rational approaches for therapeutic design, including molecularly based targeted therapies such as gene therapy and chaperone therapies.

Dr. Henry Hing Cheong Lee
Guest Editor

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Keywords

genetic epilepsy
post-traumatic epilepsy
neurodevelopmental disorder
glutamate
GABA
ionic homeostasis
disease-modifying therapy
in vitro
in vivo
animal model
gene replacement therapy
gene editing
protein misfolding
small molecule
pharmacokinetics
pharmacodynamics
translational research
biomarker
clinical trial

Published Papers (5 papers)

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Research

21 pages, 7214 KiB

Open AccessArticle

Modulating Endoplasmic Reticulum Chaperones and Mutant Protein Degradation in GABRG2(Q390X) Associated with Genetic Epilepsy with Febrile Seizures Plus and Dravet Syndrome

by Sarah Poliquin, Gerald Nwosu, Karishma Randhave, Wangzhen Shen, Carson Flamm and Jing-Qiong Kang

Int. J. Mol. Sci. 2024, 25(9), 4601; https://doi.org/10.3390/ijms25094601 - 23 Apr 2024

Viewed by 506

Abstract

A significant number of patients with genetic epilepsy do not obtain seizure freedom, despite developments in new antiseizure drugs, suggesting a need for novel therapeutic approaches. Many genetic epilepsies are associated with misfolded mutant proteins, including GABRG2(Q390X)-associated Dravet syndrome, which we have previously shown to result in intracellular accumulation of mutant GABA_A receptor γ2(Q390X) subunit protein. Thus, a potentially promising therapeutic approach is modulation of proteostasis, such as increasing endoplasmic reticulum (ER)-associated degradation (ERAD). To that end, we have here identified an ERAD-associated E3 ubiquitin ligase, HRD1, among other ubiquitin ligases, as a strong modulator of wildtype and mutant γ2 subunit expression. Overexpressing HRD1 or knockdown of HRD1 dose-dependently reduced the γ2(Q390X) subunit. Additionally, we show that zonisamide (ZNS)—an antiseizure drug reported to upregulate HRD1—reduces seizures in the Gabrg2^+/Q390X mouse. We propose that a possible mechanism for this effect is a partial rescue of surface trafficking of GABA_A receptors, which are otherwise sequestered in the ER due to the dominant-negative effect of the γ2(Q390X) subunit. Furthermore, this partial rescue was not due to changes in ER chaperones BiP and calnexin, as total expression of these chaperones was unchanged in γ2(Q390X) models. Our results here suggest that leveraging the endogenous ERAD pathway may present a potential method to degrade neurotoxic mutant proteins like the γ2(Q390X) subunit. We also demonstrate a pharmacological means of regulating proteostasis, as ZNS alters protein trafficking, providing further support for the use of proteostasis regulators for the treatment of genetic epilepsies. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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17 pages, 3513 KiB

Open AccessArticle

Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes

by Grzegorz Witkowski, Bartlomiej Szulczyk, Ewa Nurowska, Marta Jurek, Michal Pasierski, Agata Lipiec, Agnieszka Charzewska, Mateusz Dawidziuk, Michal Milewski, Szymon Owsiak, Rafal Rola, Halina Sienkiewicz Jarosz and Dorota Hoffman-Zacharska

Int. J. Mol. Sci. 2024, 25(3), 1745; https://doi.org/10.3390/ijms25031745 - 01 Feb 2024

Viewed by 696

Abstract

Mutations of the SCN1A gene, which encodes the voltage-dependent Na⁺ channel’s α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes’ variability in the family of five SCN1A gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing SCN1A-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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28 pages, 9500 KiB

Open AccessArticle

Changes in the Dentate Gyrus Gene Expression Profile Induced by Levetiracetam Treatment in Rats with Mesial Temporal Lobe Epilepsy

by Veronica Diaz-Villegas, Luz Adriana Pichardo-Macías, Sergio Juárez-Méndez, Iván Ignacio-Mejía, Noemí Cárdenas-Rodríguez, Marco Antonio Vargas-Hernández, Julieta Griselda Mendoza-Torreblanca and Sergio R. Zamudio

Int. J. Mol. Sci. 2024, 25(3), 1690; https://doi.org/10.3390/ijms25031690 - 30 Jan 2024

Viewed by 698

Abstract

Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy. Levetiracetam (LEV) is an antiepileptic drug whose mechanism of action at the genetic level has not been fully described. Therefore, the aim of the present work was to evaluate the relevant gene expression changes in the dentate gyrus (DG) of LEV-treated rats with pilocarpine-induced TLE. Whole-transcriptome microarrays were used to obtain the differential genetic profiles of control (CTRL), epileptic (EPI), and EPI rats treated for one week with LEV (EPI + LEV). Quantitative RT–qPCR was used to evaluate the RNA levels of the genes of interest. According to the results of the EPI vs. CTRL analysis, 685 genes were differentially expressed, 355 of which were underexpressed and 330 of which were overexpressed. According to the analysis of the EPI + LEV vs. EPI groups, 675 genes were differentially expressed, 477 of which were downregulated and 198 of which were upregulated. A total of 94 genes whose expression was altered by epilepsy and modified by LEV were identified. The RT–qPCR confirmed that LEV treatment reversed the increased expression of Hgf mRNA and decreased the expression of the Efcab1, Adam8, Slc24a1, and Serpinb1a genes in the DG. These results indicate that LEV could be involved in nonclassical mechanisms involved in Ca²⁺ homeostasis and the regulation of the mTOR pathway through Efcab1, Hgf, SLC24a1, Adam8, and Serpinb1a, contributing to reduced hyperexcitability in TLE patients. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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20 pages, 5745 KiB

Open AccessArticle

Effect of Vagus Nerve Stimulation on the GASH/Sal Audiogenic-Seizure-Prone Hamster

by Jaime Gonçalves-Sánchez, Consuelo Sancho, Dolores E. López, Orlando Castellano, Begoña García-Cenador, Gabriel Servilha-Menezes, Juan M. Corchado, Norberto García-Cairasco and Jesús M. Gonçalves-Estella

Int. J. Mol. Sci. 2024, 25(1), 91; https://doi.org/10.3390/ijms25010091 - 20 Dec 2023

Viewed by 745

Abstract

Vagus nerve stimulation (VNS) is an adjuvant neuromodulation therapy for the treatment of refractory epilepsy. However, the mechanisms behind its effectiveness are not fully understood. Our aim was to develop a VNS protocol for the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) in order to evaluate the mechanisms of action of the therapy. The rodents were subject to VNS for 14 days using clinical stimulation parameters by implanting a clinically available neurostimulation device or our own prototype for laboratory animals. The neuroethological assessment of seizures and general behavior were performed before surgery, and after 7, 10, and 14 days of VNS. Moreover, potential side effects were examined. Finally, the expression of 23 inflammatory markers in plasma and the left-brain hemisphere was evaluated. VNS significantly reduced seizure severity in GASH/Sal without side effects. No differences were observed between the neurostimulation devices. GASH/Sal treated with VNS showed statistically significant reduced levels of interleukin IL-1β, monocyte chemoattractant protein MCP-1, matrix metalloproteinases (MMP-2, MMP-3), and tumor necrosis factor TNF-α in the brain. The described experimental design allows for the study of VNS effects and mechanisms of action using an implantable device. This was achieved in a model of convulsive seizures in which VNS is effective and shows an anti-inflammatory effect. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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17 pages, 6392 KiB

Open AccessArticle

Enhanced Membrane Incorporation of H289Y Mutant GluK1 Receptors from the Audiogenic Seizure-Prone GASH/Sal Model: Functional and Morphological Impacts on Xenopus Oocytes

by Sandra M. Díaz-Rodríguez, Isabel Ivorra, Javier Espinosa, Celia Vegar, M. Javier Herrero-Turrión, Dolores E. López, Ricardo Gómez-Nieto and Armando Alberola-Die

Int. J. Mol. Sci. 2023, 24(23), 16852; https://doi.org/10.3390/ijms242316852 - 28 Nov 2023

Cited by 1 | Viewed by 988

Abstract

Epilepsy is a neurological disorder characterized by abnormal neuronal excitability, with glutamate playing a key role as the predominant excitatory neurotransmitter involved in seizures. Animal models of epilepsy are crucial in advancing epilepsy research by faithfully replicating the diverse symptoms of this disorder. In particular, the GASH/Sal (genetically audiogenic seizure-prone hamster from Salamanca) model exhibits seizures resembling human generalized tonic-clonic convulsions. A single nucleotide polymorphism (SNP; C9586732T, p.His289Tyr) in the Grik1 gene (which encodes the kainate receptor GluK1) has been previously identified in this strain. The H289Y mutation affects the amino-terminal domain of GluK1, which is related to the subunit assembly and trafficking. We used confocal microscopy in Xenopus oocytes to investigate how the H289Y mutation, compared to the wild type (WT), affects the expression and cell-surface trafficking of GluK1 receptors. Additionally, we employed the two-electrode voltage-clamp technique to examine the functional effects of the H289Y mutation. Our results indicate that this mutation increases the expression and incorporation of GluK1 receptors into an oocyte’s membrane, enhancing kainate-evoked currents, without affecting their functional properties. Although further research is needed to fully understand the molecular mechanisms responsible for this epilepsy, the H289Y mutation in GluK1 may be part of the molecular basis underlying the seizure-prone circuitry in the GASH/Sal model. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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