DNA Methylation Description of Hippocampus, Cortex, Amygdala, and Blood of Drug-Resistant Temporal Lobe Epilepsy

Sánchez‐Jiménez, Patricia; Elizalde-Horcada, Marcos; Sanz-García, Áncor; Granero-Cremades, Inmaculada; Toledo, María de; Pulido, Paloma Contreras; Navas, Marta; Gago-Veiga, Ana Beatriz; Alonso-Guirado, Lola; Alonso-Cerezo, María Concepción; Nava-Cedeño, Desirée; Abad‐Santos, Francisco; Torres-Díaz, Cristina Virginia; Ovejero‐Benito, María C.

doi:10.1007/s12035-022-03180-z

Cited by 8 publications

(4 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, the over-expression of histone modification and methyltransferases may support the epigenetic hypothesis of DRE 6,57–59 . There is wide evidence that inflammatory response is deeply involved in DRE 5,7,8,60–62 . Moreover, mutations on splicing sites are associated with myoclonic epilepsy 56 or epileptic encephalopathies 63 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

“Transcriptomic Profiling Unveils Novel Therapeutic Options for Drug-Resistant Temporal Lobe Epilepsy”

Sánchez-Jiménez,

Alonso-Guirado,

Cerrada-Gálvez

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundEpilepsy drug treatments fail in 25-30% of patients, who then develop drug resistance. Temporal lobe epilepsy is the most prevalent subtype associated with drug resistance. Classical drug discovery is a long and extremely costly process with a high rate of failure in clinical trials. Drug repurposing is a more cost- and time-effective strategy. Hence, the main objective of this study is to propose drug candidates for the treatment of drug-resistant temporal lobe epilepsy (DR-TLE) through drug repurposing based on transcriptomic profiling.MethodsTotal RNA-sequencing (RNA-Seq) was performed on 45 formalin-fixed paraffin-embedded (FFPE) hippocampi of DR-TLE patients and 36 FFPE hippocampi of post-mortem biobank donors. RNA-Seq was carried out in an Illumina NovaSeq 6000 platform in 100bp paired-end. Drug repurposing based on transcriptomic analysis top candidates was performed against these databases: Pandrugs2, PharmOmics, DGIdb, ToppGene, L1000CDS2and Connectivity Map.ResultsWe found 887 genes differentially expressed between DR-TLE patients and post-mortem controls. We observed 74 potential drug candidates in at least two independent databases. Of these, we selected only the 11 which can cross the blood-brain barrier: cobimetinib, panobinostat, melphalan, rucaparib, alectinib, ponatinib, danazol, carboplatin, vandetanib, erlotinib, and gefitinib. After analyzing their safety and efficacy profile based on previous publications, we provide a list of the top 5 candidates.ConclusionsWe therefore propose erlotinib, danazol, rucaparib, ponatinib, and panobinostat as potential therapies for DR-TLE based on differential RNA-Seq profiling.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Several hypotheses try to explain DRE, such as genetic variations, disease-related and drugrelated mechanisms 5 . It has been hypothesized that environmental factors and epigenetic mechanisms are involved in the development of drug resistance [6][7][8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

“Transcriptomic Profiling Unveils Novel Therapeutic Options for Drug-Resistant Temporal Lobe Epilepsy”

Sánchez-Jiménez,

Alonso-Guirado,

Cerrada-Gálvez

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…SBF1 is a target gene commonly associated with a neurological disorder, Charcot Marie Tooth disease (CMT) [52], and is highly expressed in the brain region "https://www.proteinatlas.org/ENSG00000100241-SBF1/tissue (accessed on 20 October 2022)". The clinical evidence of epilepsy in patients with CMT [53][54][55][56] and hypermethylation of SBF1 in patients with Drug-resistant Temporal Lobe Epilepsy [57] highlights the role of the SBF1 gene in epilepsy. The other gene identified in our study, BRD1, is associated with neuropsychiatric disorders such as schizophrenia and bipolar disorder along with its impact on neurodevelopmental disorders [58,59].…”

Section: Discussionmentioning

confidence: 99%

Brain Gene Co-Expression Network Analysis Identifies 22q13 Region Genes Associated with Autism, Intellectual Disability, Seizures, Language Impairment, and Hypotonia

Shah,

Sarasua,

Boccuto

et al. 2023

Genes

View full text Add to dashboard Cite

Phelan–McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder caused by 22q13 region deletions or SHANK3 gene variants. Deletions vary in size and can affect other genes in addition to SHANK3. PMS is characterized by autism spectrum disorder (ASD), intellectual disability (ID), developmental delays, seizures, speech delay, hypotonia, and minor dysmorphic features. It is challenging to determine individual gene contributions due to variability in deletion sizes and clinical features. We implemented a genomic data mining approach for identifying and prioritizing the candidate genes in the 22q13 region for five phenotypes: ASD, ID, seizures, language impairment, and hypotonia. Weighted gene co-expression networks were constructed using the BrainSpan transcriptome dataset of a human brain. Bioinformatic analyses of the co-expression modules allowed us to select specific candidate genes, including EP300, TCF20, RBX1, XPNPEP3, PMM1, SCO2, BRD1, and SHANK3, for the common neurological phenotypes of PMS. The findings help understand the disease mechanisms and may provide novel therapeutic targets for the precise treatment of PMS.

show abstract

“…In patients with MTLE, gene alterations attributed to epigenetic factors reveal distinct methylation patterns in genes responsible for voltage-gated channels, neurotransmitter receptors, and neuroinflammatory cascades within the hippocampus and amygdala. These genes participate in signaling pathways known to be associated with MTLE, including PKC activation through G-Proteins, Trk, and p75NTR neurotrophic pathways [ 103 ]. Further studies are warranted to determine the relevance and importance of differential or even inverse gene expression in the hippocampus and amygdala in patients with MTLE.…”

Section: Discussionmentioning

confidence: 99%

Clinical Correlation of Altered Molecular Signatures in Epileptic Human Hippocampus and Amygdala

Modarres Mousavi,

Alipour,

Noorbakhsh

et al. 2023

Mol Neurobiol

View full text Add to dashboard Cite

Widespread alterations in the expression of various genes could contribute to the pathogenesis of epilepsy. The expression levels of various genes, including major inhibitory and excitatory receptors, ion channels, cell type-specific markers, and excitatory amino acid transporters, were assessed and compared between the human epileptic hippocampus and amygdala, and findings from autopsy controls. Moreover, the potential correlation between molecular alterations in epileptic brain tissues and the clinical characteristics of patients undergoing epilepsy surgery was evaluated. Our findings revealed significant and complex changes in the expression of several key regulatory genes in both the hippocampus and amygdala of patients with intractable epilepsy. The expression changes in various genes differed considerably between the epileptic hippocampus and amygdala. Different correlation patterns were observed between changes in gene expression and clinical characteristics, depending on whether the patients were considered as a whole or were subdivided. Altered molecular signatures in different groups of epileptic patients, defined within a given category, could be viewed as diagnostic biomarkers. Distinct patterns of molecular changes that distinguish these groups from each other appear to be associated with epilepsy-specific functional consequences.

show abstract

DNA Methylation Description of Hippocampus, Cortex, Amygdala, and Blood of Drug-Resistant Temporal Lobe Epilepsy

Cited by 8 publications

References 60 publications

“Transcriptomic Profiling Unveils Novel Therapeutic Options for Drug-Resistant Temporal Lobe Epilepsy”

“Transcriptomic Profiling Unveils Novel Therapeutic Options for Drug-Resistant Temporal Lobe Epilepsy”

Brain Gene Co-Expression Network Analysis Identifies 22q13 Region Genes Associated with Autism, Intellectual Disability, Seizures, Language Impairment, and Hypotonia

Clinical Correlation of Altered Molecular Signatures in Epileptic Human Hippocampus and Amygdala

Contact Info

Product

Resources

About