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Genetics and Molecular Mechanisms of Epilepsy and Drug Resistance
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Genetics and Molecular Mechanisms of Epilepsy and Drug Resistance

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

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 10798

Special Issue Editors

Dr. Nigel Jones

E-Mail Website
Guest Editor
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Interests: epilepsy
Prof. Dr. Patrick Kwan

E-Mail Website
Guest Editor
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Interests: epilepsy; neurology; genomics; lab-on-a-chip; wearable device
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Epilepsy represents a group of chronic neurological disorders characterised by persisting unprovoked epileptic seizures. Affecting more than 50 million people of both sexes and across all ages, it contributes to more than 0.5% of the global disease burden. Despite the continuous development of new antiseizure medications, approximately 30% of those affected do not respond to currently available pharmacological treatments. Comorbidities such as depression, anxiety, cardiovascular disease, and neurodevelopmental disorders are common, and epileptic activity may contribute to cognitive and behavioural impairments. Those living with epilepsy have a reduced quality of life due to non-medical factors such as stigmatisation and reduced ability to maintain employment, and the societal costs for those living with epilepsy are considerable. Epilepsy can arise due to inherited or de novo genetic mutations or may develop following brain insult, such as a stroke, infection, or tumour; however, in many cases its aetiology is unknown. Our understanding of the molecular underpinnings of epilepsy remains incomplete, and investigations are challenged by the heterogenous nature of the disorder. The mechanisms of pharmacoresistance are poorly understood. This Special Issue aims to bring together research from a wide range of perspectives. This cross-silo approach will help to illuminate relationships between disparate factors that contribute to seizure activity or that modify treatment response.

Suggested sub-topics:

  • A role for the gut microbiome in the treatment of epilepsy;
  • The dysregulation of circadian networks in patients with epilepsy;
  • Brain in a dish models of epilepsy;
  • Molecular mechanisms in epilepsy aetiologies;
  • Gene regulatory networks in epilepsy;
  • Molecular and genetic mechanisms of drug resistance in epilepsy;
  • Application of machine learning to elucidate the molecular mechanisms of epilepsy and drug resistance.

Dr. Nigel Jones
Prof. Dr. Patrick Kwan
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (3 papers)

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Research

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19 pages, 3195 KiB  
Article
An Integrated Multi-Omic Network Analysis Identifies Seizure-Associated Dysregulated Pathways in the GAERS Model of Absence Epilepsy
by Anna Harutyunyan, Debbie Chong, Rui Li, Anup D. Shah, Zahra Ali, Cheng Huang, Christopher K. Barlow, Piero Perucca, Terence J. O’Brien, Nigel C. Jones, Ralf B. Schittenhelm, Alison Anderson and Pablo M. Casillas-Espinosa
Int. J. Mol. Sci. 2022, 23(11), 6063; https://doi.org/10.3390/ijms23116063 - 28 May 2022
Cited by 12 | Viewed by 3483
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Genetics and Molecular Mechanisms of Epilepsy and Drug Resistance)
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Review

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21 pages, 793 KiB  
Review
Potential Roles for the GluN2D NMDA Receptor Subunit in Schizophrenia
by Chitra Vinnakota, Matthew R. Hudson, Nigel C. Jones, Suresh Sundram and Rachel A. Hill
Int. J. Mol. Sci. 2023, 24(14), 11835; https://doi.org/10.3390/ijms241411835 - 23 Jul 2023
Cited by 1 | Viewed by 3277
Abstract
Glutamate N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie schizophrenia symptoms. This theory arose from the observation that administration of NMDAR antagonists, which are compounds that inhibit NMDAR activity, reproduces behavioural and molecular schizophrenia-like phenotypes, including hallucinations, delusions and cognitive impairments [...] Read more.
Glutamate N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie schizophrenia symptoms. This theory arose from the observation that administration of NMDAR antagonists, which are compounds that inhibit NMDAR activity, reproduces behavioural and molecular schizophrenia-like phenotypes, including hallucinations, delusions and cognitive impairments in healthy humans and animal models. However, the role of specific NMDAR subunits in these schizophrenia-relevant phenotypes is largely unknown. Mounting evidence implicates the GluN2D subunit of NMDAR in some of these symptoms and pathology. Firstly, genetic and post-mortem studies show changes in the GluN2D subunit in people with schizophrenia. Secondly, the psychosis-inducing effects of NMDAR antagonists are blunted in GluN2D-knockout mice, suggesting that the GluN2D subunit mediates NMDAR-antagonist-induced psychotomimetic effects. Thirdly, in the mature brain, the GluN2D subunit is relatively enriched in parvalbumin (PV)-containing interneurons, a cell type hypothesized to underlie the cognitive symptoms of schizophrenia. Lastly, the GluN2D subunit is widely and abundantly expressed early in development, which could be of importance considering schizophrenia is a disorder that has its origins in early neurodevelopment. The limitations of currently available therapies warrant further research into novel therapeutic targets such as the GluN2D subunit, which may help us better understand underlying disease mechanisms and develop novel and more effective treatment options. Full article
(This article belongs to the Special Issue Genetics and Molecular Mechanisms of Epilepsy and Drug Resistance)
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15 pages, 441 KiB  
Review
CfDNA Measurement as a Diagnostic Tool for the Detection of Brain Somatic Mutations in Refractory Epilepsy
by Sonia Mayo, Irene Gómez-Manjón, Francisco Javier Fernández-Martínez, Ana Camacho, Francisco Martínez and Julián Benito-León
Int. J. Mol. Sci. 2022, 23(9), 4879; https://doi.org/10.3390/ijms23094879 - 28 Apr 2022
Cited by 3 | Viewed by 3051
Abstract
Epilepsy is a neurological disorder that affects more than 50 million people. Its etiology is unknown in approximately 60% of cases, although the existence of a genetic factor is estimated in about 75% of these individuals. Hundreds of genes involved in epilepsy are [...] Read more.
Epilepsy is a neurological disorder that affects more than 50 million people. Its etiology is unknown in approximately 60% of cases, although the existence of a genetic factor is estimated in about 75% of these individuals. Hundreds of genes involved in epilepsy are known, and their number is increasing progressively, especially with next-generation sequencing techniques. However, there are still many cases in which the results of these molecular studies do not fully explain the phenotype of the patients. Somatic mutations specific to brain tissue could contribute to the phenotypic spectrum of epilepsy. Undetectable in the genomic DNA of blood cells, these alterations can be identified in cell-free DNA (cfDNA). We aim to review the current literature regarding the detection of somatic variants in cfDNA to diagnose refractory epilepsy, highlighting novel research directions and suggesting further studies. Full article
(This article belongs to the Special Issue Genetics and Molecular Mechanisms of Epilepsy and Drug Resistance)
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