Polyadenylation of mRNA as a novel regulatory mechanism of gene expression in temporal lobe epilepsy

Abstract Temporal lobe epilepsy is the most common and refractory form of epilepsy in adults. Gene expression within affected structures such as the hippocampus displays extensive dysregulation and is implicated as a central pathomechanism. Post-transcriptional mechanisms are increasingly recognized as determinants of the gene expression landscape, but key mechanisms remain unexplored. Here we show, for first time, that cytoplasmic mRNA polyadenylation, one of the post-transcriptional mechanisms regulating gene expression, undergoes widespread reorganization in temporal lobe epilepsy. In the hippocampus of mice subjected to status epilepticus and epilepsy, we report >25% of the transcriptome displays changes in their poly(A) tail length, with deadenylation disproportionately affecting genes previously associated with epilepsy. Suggesting cytoplasmic polyadenylation element binding proteins (CPEBs) being one of the main contributors to mRNA polyadenylation changes, transcripts targeted by CPEBs were particularly enriched among the gene pool undergoing poly(A) tail alterations during epilepsy. Transcripts bound by CPEB4 were over-represented among transcripts with poly(A) tail alterations and epilepsy-related genes and CPEB4 expression was found to be increased in mouse models of seizures and resected hippocampi from patients with drug-refractory temporal lobe epilepsy. Finally, supporting an adaptive function for CPEB4, deletion of Cpeb4 exacerbated seizure severity and neurodegeneration during status epilepticus and the development of epilepsy in mice. Together, these findings reveal an additional layer of gene expression regulation during epilepsy and point to novel targets for seizure control and disease-modification in epilepsy.

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High concordance between hippocampal transcriptome of the intraamygdala kainic acid model and human temporal lobe epilepsy

10.1101/2020.05.12.092338 ◽

2020 ◽

Author(s):

Giorgia Conte ◽

Alberto Parras ◽

Mariana Alves ◽

Ivana Ollà ◽

Laura de Diego-Garcia ◽

...

Keyword(s):

Gene Expression ◽

Status Epilepticus ◽

Temporal Lobe Epilepsy ◽

Kainic Acid ◽

Temporal Lobe ◽

Calcium Signalling ◽

Experimental Models ◽

Drug Resistant ◽

The Brain ◽

Models Of Epilepsy

AbstractObjectivePharmacoresistance and the lack of disease-modifying actions of current anti-seizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant-induced status epilepticus remain the models of choice to discover potential anti-epileptogenic drugs but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intraamygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug-resistant temporal lobe epilepsy (TLE).MethodsStatus epilepticus was induced via intraamygdala microinjection of kainic acid in C57BL/6 mice and gene expression analysed via microarrays in hippocampal tissue at acute and chronic time-points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug-resistant TLE.ResultsIntraamygdala kainic acid injection in mice triggered extensive dysregulation of gene expression which was ∼3-fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples of patients with TLE revealed a particular high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signalling to be highly conserved across different models of epilepsy and patients. CREB was predicted as one of the main up-stream transcription factors regulating gene expression during acute and chronic phases and inhibition of CREB reduced seizure severity in the intraamygdala kainic acid model.SignificanceOur findings suggest the intraamygdala kainic acid model faithfully replicates key molecular features of human drug-resistant temporal lobe epilepsy and provides potential rationale target approaches for disease-modification through new insights into the unique and shared gene expression landscape in experimental epilepsy.Key point boxMore genes show expression changes shortly following intraamygdala kainic acid-induced status epilepticus when compared to established epilepsy.The intraamygdala kainic acid mouse model mimics closely the gene expression landscape in the brain of patients with temporal lobe epilepsy.Supressed calcium signalling in the brain as common feature across experimental models of epilepsy and patients with temporal lobe epilepsy.CREB is a major up-stream transcription factor during early changes following status epilepticus and once epilepsy is established.

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Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

10.1101/725325 ◽

2019 ◽

Author(s):

Alberto Parras ◽

Laura de Diego-Garcia ◽

Mariana Alves ◽

Edward Beamer ◽

Giorgia Conte ◽

...

Keyword(s):

Gene Expression ◽

Temporal Lobe Epilepsy ◽

Mouse Models ◽

Temporal Lobe ◽

Large Scale ◽

Molecular Mechanisms ◽

Chronic Phase ◽

Gene Expression Control ◽

Mrna Polyadenylation ◽

Models Of Epilepsy

AbstractThe molecular mechanisms that shape the gene expression landscape during the development and maintenance of chronic states of brain hyperexcitability are incompletely understood. Here we show that cytoplasmic mRNA polyadenylation, a posttranscriptional mechanism for regulating gene expression, undergoes widespread reorganisation in temporal lobe epilepsy. Specifically, over 25% of the hippocampal transcriptome displayed changes in their poly(A) tail in mouse models of epilepsy, particular evident in the chronic phase. The expression of cytoplasmic polyadenylation binding proteins (CPEB1-4) was found to be altered in the hippocampus in mouse models of epilepsy and temporal lobe epilepsy patients and CPEB4 target transcripts were over-represented among those showing poly(A) tail changes. Supporting an adaptive function, CPEB4-deficiency leads to an increase in seizure severity and neurodegeneration in mouse models of epilepsy. Together, these findings reveal an additional layer of gene expression control during epilepsy and point to novel targets for seizure control and disease-modification in epilepsy.

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Prophylactic treatment with melatonin after status epilepticus: Effects on epileptogenesis, neuronal damage, and behavioral changes in a kainate model of temporal lobe epilepsy

Epilepsy & Behavior ◽

10.1016/j.yebeh.2013.01.009 ◽

2013 ◽

Vol 27 (1) ◽

pp. 174-187 ◽

Cited By ~ 35

Author(s):

Jana Tchekalarova ◽

Zlatina Petkova ◽

Daniela Pechlivanova ◽

Slavianka Moyanova ◽

Lidia Kortenska ◽

...

Keyword(s):

Status Epilepticus ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Prophylactic Treatment ◽

Neuronal Damage ◽

Behavioral Changes

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Induction of the Nrf2 Pathway by Sulforaphane Is Neuroprotective in a Rat Temporal Lobe Epilepsy Model

Antioxidants ◽

10.3390/antiox10111702 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1702

Author(s):

Sereen Sandouka ◽

Tawfeeq Shekh-Ahmad

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Status Epilepticus ◽

Temporal Lobe Epilepsy ◽

Antioxidant Capacity ◽

Temporal Lobe ◽

Epileptiform Activity ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

The Brain

Epilepsy is a chronic disease of the brain that affects over 65 million people worldwide. Acquired epilepsy is initiated by neurological insults, such as status epilepticus, which can result in the generation of ROS and induction of oxidative stress. Suppressing oxidative stress by upregulation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to be an effective strategy to increase endogenous antioxidant defences, including in brain diseases, and can ameliorate neuronal damage and seizure occurrence in epilepsy. Here, we aim to test the neuroprotective potential of a naturally occurring Nrf2 activator sulforaphane, in in vitro epileptiform activity model and a temporal lobe epilepsy rat model. Sulforaphane significantly decreased ROS generation during epileptiform activity, restored glutathione levels, and prevented seizure-like activity-induced neuronal cell death. When given to rats after 2 h of kainic acid-induced status epilepticus, sulforaphane significantly increased the expression of Nrf2 and related antioxidant genes, improved oxidative stress markers, and increased the total antioxidant capacity in both the plasma and hippocampus. In addition, sulforaphane significantly decreased status epilepticus-induced neuronal cell death. Our results demonstrate that Nrf2 activation following an insult to the brain exerts a neuroprotective effect by reducing neuronal death, increasing the antioxidant capacity, and thus may also modify epilepsy development.

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Close relationship between initial convulsive status epilepticus in early childhood and the later development of mesial temporal lobe epilepsy

Brain and Development ◽

10.1016/s0387-7604(97)82996-8 ◽

1996 ◽

Vol 18 (6) ◽

pp. 472 ◽

Cited By ~ 1

Author(s):

Tateki Fujiwara ◽

Takayasu Tottori ◽

Yuko Kuboto ◽

Kazumi Matsuda ◽

Tadahiro Mihara ◽

...

Keyword(s):

Early Childhood ◽

Status Epilepticus ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Mesial Temporal Lobe Epilepsy ◽

Convulsive Status Epilepticus ◽

Close Relationship ◽

Mesial Temporal Lobe

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Grafting of striatal precursor cells into hippocampus shortly after status epilepticus restrains chronic temporal lobe epilepsy

Experimental Neurology ◽

10.1016/j.expneurol.2008.04.040 ◽

2008 ◽

Vol 212 (2) ◽

pp. 468-481 ◽

Cited By ~ 64

Author(s):

Bharathi Hattiangady ◽

Muddanna S. Rao ◽

Ashok K. Shetty

Keyword(s):

Status Epilepticus ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Precursor Cells

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Animal models of status epilepticus and temporal lobe epilepsy: a narrative review

Reviews in the Neurosciences ◽

10.1515/revneuro-2017-0086 ◽

2018 ◽

Vol 29 (7) ◽

pp. 757-770 ◽

Cited By ~ 11

Author(s):

Nikita Nirwan ◽

Preeti Vyas ◽

Divya Vohora

Keyword(s):

Animal Model ◽

Status Epilepticus ◽

Animal Models ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Current Literature ◽

Clinical Characteristics ◽

Genetic Models ◽

Suitable Animal Model ◽

Effective Models

Abstract Temporal lobe epilepsy (TLE) is the chronic and pharmacoresistant form of epilepsy observed in humans. The current literature is insufficient in explicating the comprehensive mechanisms underlying its pathogenesis and advancement. Consequently, the development of a suitable animal model mimicking the clinical characteristics is required. Further, the relevance of status epilepticus (SE) to animal models is dubious. SE occurs rarely in people; most epilepsy patients never experience it. The present review summarizes the established animal models of SE and TLE, along with a brief discussion of the animal models that have the distinctiveness and carries the possibility to be developed as effective models for TLE. The review not only covers the basic requirements, mechanisms, and methods of induction of each model but also focuses upon their major limitations and possible modifications for their future use. A detailed discussion on chemical, electrical, and hypoxic/ischemic models as well as a brief explanation on the genetic models, most of which are characterized by development of SE followed by neurodegeneration, is presented.

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