Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress has been identified as the significant mediator in epilepsy, which is a chronic disorder in central nervous system. About 30% of epilepsy patients are refractory to antiepileptic drug treatment. However, the underlying mechanism of oxidative damage in epilepsy needs further investigation. In our study, we first find that ubiquitin-specific peptidase 15 (USP15) expression was upregulated in a pentylenetetrazole (PTZ) kindled rat model of epilepsy. Silencing USP15 protected against glutamate-mediated neuronal cell death, and inhibited the high expression levels of cleaved caspase-3. Knockout of USP15 significantly reduced intracellular reactive oxygen species (ROS) levels and enhanced superoxide dismutase (SOD) activity in HT22 cells under the exposure to glutamate treatment. Furthermore, USP15 inhibition induced nuclear factor erythroid-derived 2-related factor2 (Nrf2) nuclear translocation and promoted protein expression level of heme oxygenase (HO-1). Taken together, our findings first reveal a role of USP15 in the pathogenesis of epilepsy, and silencing USP15 in vitro protects against glutamate-mediated cytotoxicity in HT22 cells. Pharmacological inhibition of USP15 may alleviate epileptic seizures via fighting against oxidative damage, providing a novel antiepileptic target.
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PMID:Inhibition of USP15 Prevent Glutamate-Induced Oxidative Damage by Activating Nrf2/HO-1 Signaling Pathway in HT22 Cells. 3193 62

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am-/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3am+/p- paternal transmission cohort. We also discovered Ube3am-/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3am-/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3am+/p- did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS.
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PMID:Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome. 3206 85

Recent evidence suggests that autophagy impairment is implicated in the epileptogenic mechanisms downstream of mTOR hyperactivation. This holds true for a variety of genetic and acquired epileptic syndromes besides malformations of cortical development which are classically known as mTORopathies. Autophagy suppression is sufficient to induce epilepsy in experimental models, while rescuing autophagy prevents epileptogenesis, improves behavioral alterations, and provides neuroprotection in seizure-induced neuronal damage. The implication of autophagy in epileptogenesis and maturation phenomena related to seizure activity is supported by evidence indicating that autophagy is involved in the molecular mechanisms which are implicated in epilepsy. In general, mTOR-dependent autophagy regulates the proliferation and migration of inter-/neuronal cortical progenitors, synapse development, vesicular release, synaptic plasticity, and importantly, synaptic clustering of GABAA receptors and subsequent excitatory/inhibitory balance in the brain. Similar to autophagy, the ubiquitin-proteasome system is regulated downstream of mTOR, and it is implicated in epileptogenesis. Thus, mTOR-dependent cell-clearing systems are now taking center stage in the field of epilepsy. In the present review, we discuss such evidence in a variety of seizure-related disorders and models. This is expected to provide a deeper insight into the molecular mechanisms underlying seizure activity.
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PMID:mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update. 3212 Dec 50

Brain injuries are associated with oxidative stress and a need to restore neuronal homeostasis. Mutations in ion channel genes, in particular CACNA1A, have been implicated in familial hemiplegic migraine (FHM) and in the development of concussion-related symptoms in response to trivial head trauma. The aim of this study was to explore the potential role of variants in other ion channel genes in the development of such responses. We conducted whole exome sequencing (WES) on16 individuals who developed a range of neurological and concussion-related symptoms following minor or trivial head injuries. All individuals were initially tested and shown to be negative for mutations in known FHM genes. Variants identified from the WES results were filtered to identify rare variants (minor allele frequency [MAF] <0.01) in genes related to neural processes as well as genes highly expressed in the brain using a combination of in silico prediction tools (SIFT, PolyPhen, PredictSNP, Mutation Taster, and Mutation Assessor). Rare (MAF <0.001) or novel heterozygous variants in 7 ion channel genes were identified in 37.5% (6/16) of the cases (CACNA1I, CACNA1C, ATP10A, ATP7B, KCNAB1, KCNJ10, and SLC26A4), rare variants in neurotransmitter genes were found in 2 cases (GABRG1 and GRIK1), and rare variants in 3 ubiquitin-related genes identified in 4 cases (SQSTM1, TRIM2, and HECTD1). In this study, the largest proportion of potentially pathogenic variants in individuals with severe responses to minor head trauma were identified in genes previously implicated in migraine and seizure-related autosomal recessive neurological disorders. Together with results implicating variants in the hemiplegic migraine genes, CACNA1A and ATP1A2, in severe head trauma response, our results support a role for heterozygous deleterious mutations in genes implicated in neurological dysfunction and potentially increasing the risk of poor response to trivial head trauma.
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PMID:Exploring Neuronal Vulnerability to Head Trauma Using a Whole Exome Approach. 3223 32

Environmental toxicants have the potential to contribute to the pathophysiology of multiple complex diseases, but the underlying mechanisms remain obscure. One such toxicant is the widely used fungicide ziram, a dithiocarbamate known to have neurotoxic effects and to increase the risk of Parkinson's disease. We have used Drosophila melanogaster as an unbiased discovery tool to identify novel molecular pathways by which ziram may disrupt neuronal function. Consistent with previous results in mammalian cells, we find that ziram increases the probability of synaptic vesicle release by dysregulation of the ubiquitin signaling system. In addition, we find that ziram increases neuronal excitability. Using a combination of live imaging and electrophysiology, we find that ziram increases excitability in both aminergic and glutamatergic neurons. This increased excitability is phenocopied and occluded by null mutant animals of the ether a-go-go (eag) potassium channel. A pharmacological inhibitor of the temperature sensitive hERG (human ether-a-go-go related gene) phenocopies the excitability effects of ziram but only at elevated temperatures. seizure (sei), a fly ortholog of hERG, is thus another candidate target of ziram. Taken together, the eag family of potassium channels emerges as a candidate for mediating some of the toxic effects of ziram. We propose that ziram may contribute to the risk of complex human diseases by blockade of human eag and sei orthologs, such as hERG.
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PMID:The environmental toxicant ziram enhances neurotransmitter release and increases neuronal excitability via the EAG family of potassium channels. 3255 9

Sentrin/small ubiquitin-like modifier (SUMO) is protein modification pathway that regulates multiple biological processes, including cell division, DNA replication/repair, signal transduction, and cellular metabolism. In this review, we will focus on recent advances in the mechanisms of disease pathogenesis, such as cancer, diabetes, seizure, and heart failure, which have been linked to the SUMO pathway. SUMO is conjugated to lysine residues in target proteins through an isopeptide linkage catalyzed by SUMO-specific activating (E1), conjugating (E2), and ligating (E3) enzymes. In steady state, the quantity of SUMO-modified substrates is usually a small fraction of unmodified substrates due to the deconjugation activity of the family Sentrin/SUMO-specific proteases (SENPs). In contrast to the complexity of the ubiquitination/deubiquitination machinery, the biochemistry of SUMOylation and de-SUMOylation is relatively modest. Specificity of the SUMO pathway is achieved through redox regulation, acetylation, phosphorylation, or other posttranslational protein modification of the SUMOylation and de-SUMOylation enzymes. There are three major SUMOs. SUMO-1 usually modifies a substrate as a monomer; however, SUMO-2/3 can form poly-SUMO chains. The monomeric SUMO-1 or poly-SUMO chains can interact with other proteins through SUMO-interactive motif (SIM). Thus SUMO modification provides a platform to enhance protein-protein interaction. The consequence of SUMOylation includes changes in cellular localization, protein activity, or protein stability. Furthermore, SUMO may join force with ubiquitin to degrade proteins through SUMO-targeted ubiquitin ligases (STUbL). After 20 yr of research, SUMO has been shown to play critical roles in most, if not all, biological pathways. Thus the SUMO enzymes could be targets for drug development to treat human diseases.
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PMID:SUMO: From Bench to Bedside. 3266 86

Focal neuronal lipofuscinosis is a unique neuronal pathology, characterised by accumulation of lipofuscin within dysmorphic neurons. We report a case of 12-year-old female with drug resistant epilepsy since one and a half years of age. MRI brain showed right frontal dysplasia, and PET showed right frontal hypometabolism. She underwent electrocorticography-guided resection of the lesion. Histopathology revealed cortical dyslamination with several hypertrophic dysmorphic neurons showing intracytoplasmic granular accumulation of lipofuscin which was positive for Periodic acid-Schiff, Luxol fast blue, and autofluorescent. Ultrastructural examination revealed intracytoplasmic, non-membrane bound, electron dense material with characteristics of lipofuscin filling the neuronal soma. On immunohistochemistry, the neurons showed ring-like non-phosphorylated and phosphorylated neurofilaments enveloping the lipofuscin material, few being positive for ubiquitin. It is important to be aware of this rare entity as it can be associated with family history of seizures and has a distinct pathobiology.
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PMID:Frontal lobe epilepsy with focal neuronal lipofuscinosis - Case report of a rare entity. 3274 41


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