Epilepsy: new genes, new technologies, new insights

Lee, Ki Young; Heo, Kyoung

doi:10.1016/s1474-4422(13)70240-0

Cited by 7 publications

(4 citation statements)

References 5 publications

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“…Epilepsy is a chronic neurological condition affecting around 1% of the global population and is characterized by recurrent spontaneous seizures with potential comorbidities [1,2]. Epileptogenesis is generally initiated by an inciting event, such as a prolonged seizure called status epilepticus (SE), brain tumors, head injury, infection, or other causes.…”

Section: Introductionmentioning

confidence: 99%

A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis

Alqurashi

Yee²,

Malone

et al. 2021

PLoS ONE

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Epilepsy is a complex neurological condition characterized by repeated spontaneous seizures and can be induced by initiating seizures known as status epilepticus (SE). Elaborating the critical molecular mechanisms following SE are central to understanding the establishment of chronic seizures. Here, we identify a transient program of molecular and metabolic signaling in the early epileptogenic period, centered on day five following SE in the pre-clinical kainate or pilocarpine models of temporal lobe epilepsy. Our work now elaborates a new molecular mechanism centered around Wnt signaling and a growing network comprised of metabolic reprogramming and mTOR activation. Biochemical, metabolomic, confocal microscopy and mouse genetics experiments all demonstrate coordinated activation of Wnt signaling, predominantly in neurons, and the ensuing induction of an overall aerobic glycolysis (Warburg-like phenomenon) and an altered TCA cycle in early epileptogenesis. A centerpiece of the mechanism is the regulation of pyruvate dehydrogenase (PDH) through its kinase and Wnt target genes PDK4. Intriguingly, PDH is a central gene in certain genetic epilepsies, underscoring the relevance of our elaborated mechanisms. While sharing some features with cancers, the Warburg-like metabolism in early epileptogenesis is uniquely split between neurons and astrocytes to achieve an overall novel metabolic reprogramming. This split Warburg metabolic reprogramming triggers an inhibition of AMPK and subsequent activation of mTOR, which is a signature event of epileptogenesis. Interrogation of the mechanism with the metabolic inhibitor 2-deoxyglucose surprisingly demonstrated that Wnt signaling and the resulting metabolic reprogramming lies upstream of mTOR activation in epileptogenesis. To augment the pre-clinical pilocarpine and kainate models, aspects of the proposed mechanisms were also investigated and correlated in a genetic model of constitutive Wnt signaling (deletion of the transcriptional repressor and Wnt pathway inhibitor HBP1). The results from the HBP1-/- mice provide a genetic evidence that Wnt signaling may set the threshold of acquired seizure susceptibility with a similar molecular framework. Using biochemistry and genetics, this paper outlines a new molecular framework of early epileptogenesis and advances a potential molecular platform for refining therapeutic strategies in attenuating recurrent seizures.

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Section: Introductionmentioning

confidence: 99%

A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis

Alqurashi

Yee²,

Malone

et al. 2021

PLoS ONE

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“…With the development of genetic discoveries and genetic techniques, molecular causes of epilepsy has been comprehensively revealed during the past several years ( Buiting et al, 1995 ; Buiting, 2010 ; Lee and Heo, 2014 ; El Achkar et al, 2015 ). Emerging evidence infers the participation of microRNAs (miRs) in the lesion of types of epilepsy ( Li et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Antagonist Targeting microRNA-155 Protects against Lithium-Pilocarpine-Induced Status Epilepticus in C57BL/6 Mice by Activating Brain-Derived Neurotrophic Factor

Cai

et al. 2016

Front. Pharmacol.

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Epilepsy is a severe brain disorder affecting numerous patients. Recently, it is inferred that modulation of microRNA-155 (miR-155) could serve as a promising treatment of mesial temporal lobe epilepsy. In the current study, the therapeutic potential of miR-155 antagonist against temporal lobe epilepsy (TLE) was evaluated and the underlying mechanism involved in this regulation was explored. TLE model was induced by lithium-pilocarpine method. The effect of miR-155 antagonist on epilepticus symptoms of TLE mice was assessed using Racine classification and electroencephalogram (EEG) recordings. The expression of brain-derived neurotrophic factor (BDNF) and its association with miR-155 were also assessed with a series of experiments. Our results showed that level of miR-155 was significantly up-regulated after induction of TLE model. Based on the results of EEG and behavior analyses, seizures in mice were alleviated by miR-155 antagonist. Moreover, administration of miR-155 antagonist also significantly increased the level of BDNF. The results of dual luciferase assay and Western blotting showed that miR-155 antagonist exerted its action on status epilepticus by directly regulating the activity of BDNF. Taken all the information together, our results demonstrated that miR-155 antagonist might firstly induce the expression of BDNF, which then contributed to the alleviation of epilepsy in the current study.

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“…The list of single genes linked to epilepsy is expanding rapidly, promising to revolutionize the way we diagnose and treat hereditary seizure disorders (Ferraro 2012;Lee and Heo 2014;Martin et al 2014;Myers and Mefford 2015). These monogenic disorders, numbering close to 150 by recent count, arise in families with a sufficiently informative pedigree that allows a highly penetrant mutation to be localized by conventional mapping and sequencing techniques.…”

Section: The Epilepsy Genomementioning

confidence: 99%

The Epilepsy Spectrum: Targeting Future Research Challenges

Holmes

Noebels

2016

Cold Spring Harb Perspect Med

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There have been tremendous recent advances in our understanding of the biological underpinnings of epilepsy and associated comorbidities that justify its representation as a spectrum disorder. Advances in genetics, electrophysiology, and neuroimaging have greatly improved our ability to differentiate, diagnose, and treat individuals with epilepsy. However, we have made little overall progress in preventing epilepsy, and the number of patients who are cured remains small. Likewise, the comorbidities of epilepsy are often underdiagnosed or not adequately treated. In this article, we suggest a few areas in which additional research will likely pay big dividends for patients and their families.T he pace of recent advances in epilepsy has been explosive, driven by our increasing understanding of the disorder's inextricable links to development, excitability, and plasticity in the central nervous system, and by the steady emergence of techniques to analyze these properties at high resolution in both human and animal models. As shown in Figure 1, there has been a near doubling in published articles dealing with epilepsy over the last 15 years. Experimental research has produced a threefold increase in peer-reviewed papers since 1970. Subareas within epilepsy research that have shown nearly exponential increases in activity include genetic models, epileptogenesis, comorbidities, and mortality.Although it is gratifying that epilepsy is now receiving the attention it deserves based on its prevalence, the new knowledge comes at a cost; the more we learn about the complex biology of epilepsy, the further away we appear to be from the therapeutic goalposts. Despite our advances in more precisely defining seizure phenotypes, isolating causative genes, and developing specific therapies, much more work needs to be done before we can hope to prevent epilepsy in vulnerable populations, reduce comorbidities associated with epilepsy, and effectively eliminate seizures without causing adverse side effects. However, clinical heterogeneity and molecular complexity are features of all human disease, and serve to position the field of epilepsy research alongside that of cancer in allowing the opportunity to make steady inroads in curing certain forms (Noebels 2015). In the future, rather than measuring our progress by the prevalence of the disorder as a whole, we will be monitoring research progress within the many

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Epilepsy: new genes, new technologies, new insights

Cited by 7 publications

References 5 publications

A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis

A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis

Antagonist Targeting microRNA-155 Protects against Lithium-Pilocarpine-Induced Status Epilepticus in C57BL/6 Mice by Activating Brain-Derived Neurotrophic Factor

The Epilepsy Spectrum: Targeting Future Research Challenges

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