Molecular mechanisms of epilepsy

Staley, Kevin J.

doi:10.1038/nn.3947

Cited by 325 publications

(287 citation statements)

References 80 publications

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“…Epilepsy is a heterogeneous collection of seizure disorders that result from different underlying defects in neuronal membrane excitability and synaptic function (Staley, 2015). These phenotypic variances can be influenced by dysregulation of ion channels (Armijo et al, 2005), neurotransmitter systems (Masino et al, 2014; Rowley et al, 2012), neuropeptides (Kovac and Walker, 2013), hormones (Tauboll et al, 2015), ion transporters (Cox et al, 1997; Kahle et al, 2008), calcium-activated kinases (Butler et al, 1995), and/or vesicle release proteins (Rosahl et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Zhao

Carney

Falgoust

et al. 2016

Progress in Neurobiology

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Epilepsy is a common central nervous system (CNS) disease characterized by recurrent transient neurological events occurring due to abnormally excessive or synchronous neuronal activity in the brain. The CNS is affected by systemic acid–base disorders, and epileptic seizures are sensitive indicators of underlying imbalances in cellular pH regulation. Na+/H+ exchangers (NHEs) are a family of membrane transporter proteins actively involved in regulating intracellular and organellar pH by extruding H+ in exchange for Na+ influx. Altering NHE function significantly influences neuronal excitability and plays a role in epilepsy. This review gives an overview of pH regulatory mechanisms in the brain with a special focus on the NHE family and the relationship between epilepsy and dysfunction of NHE isoforms. We first discuss how cells translocate acids and bases across the membrane and establish pH homeostasis as a result of the concerted effort of enzymes and ion transporters. We focus on the specific roles of the NHE family by detailing how the loss of NHE1 in two NHE mutant mice results in enhanced neuronal excitability in these animals. Furthermore, we highlight new findings on the link between mutations of NHE6 and NHE9 and developmental brain disorders including epilepsy, autism, and attention deficit hyperactivity disorder (ADHD). These studies demonstrate the importance of NHE proteins in maintaining H+ homeostasis and their intricate roles in the regulation of neuronal function. A better understanding of the mechanisms underlying NHE1, 6, and 9 dysfunctions in epilepsy formation may advance the development of new epilepsy treatment strategies.

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Section: Introductionmentioning

confidence: 99%

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Zhao

Carney

Falgoust

et al. 2016

Progress in Neurobiology

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“…Epilepsy is a severe neurological disorder characterized mainly by recurrent seizures due to an abnormal neuronal hyperexcitability in the brain and according to the World Health Organization, affects approximately 50 million people worldwide [1,2].…”

Section: Introductionmentioning

confidence: 99%

Anticonvulsant and behavioral effects observed in mice following treatment with an ester derivative of ferulic acid: Isopentyl ferulate

Machado

Oliveira

Machado

et al. 2015

Chemico-Biological Interactions

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“…The current state of known mechanisms of epilepsy and the range of available treatments suggest additional pathways and mechanisms responsible for currently intractable cases of epilepsy. This underscores the importance of more research needed to better understand the underlying disease mechanisms and identify novel drug targets or treatment strategies (4). We present available evidence for the potential role of epigenetic mechanisms and certain naturally unfolded proteins (NUPs) that may create pores in cell membranes and contribute to dysregulated ion flows that characterize electric discharges.…”

Section: Introductionmentioning

confidence: 99%

Pore-Forming Proteins as Mediators of Novel Epigenetic Mechanism of Epilepsy

et al. 2017

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Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. In the last two decades, numerous gene defects underlying different forms of epilepsy have been identified with most of these genes encoding ion channel proteins. Despite these developments, the etiology of majority of non-familial epilepsies has no known associated genetic mutations and cannot be explained by defects in identified ion channels alone. We hypothesize that de novo formation of ion channels by naturally unfolded proteins (NUPs) increases neuronal excitability. Altered ionic homeostasis may initiate/contribute to cellular cascades related to epileptogenesis in susceptible individuals. Here, we consider two small proteins, namely, α-synuclein and stefin B, as prototypical candidates to illustrate the underlying mechanism(s). Previous work points to an association between epilepsy and α-synuclein or stefin B, but the mechanism(s) underlying such association remains elusive. We review the evidence to link the structure–function of these proteins with disease processes. Epigenetic mechanisms unrelated to altered DNA sequence(s) that may affect epileptogenesis include transcriptional or posttranscriptional regulation. Such epigenetic mechanisms or their combination(s) enhance the levels of these proteins and as a result the ability to form annular structures, which upon incorporation into membrane form novel ion channels and disturb intracellular ion homeostasis. Alternative epigenetic mechanisms may change amyloidogenic proteins by posttranslational modifications, thereby increasing their propensity to form channels. Further research elucidating the details about the formation of ion channels through these mechanisms and their role in epileptogenesis may define new molecular targets and guide the development of new drug targets.

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Molecular mechanisms of epilepsy

Cited by 325 publications

References 80 publications

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Anticonvulsant and behavioral effects observed in mice following treatment with an ester derivative of ferulic acid: Isopentyl ferulate

Pore-Forming Proteins as Mediators of Novel Epigenetic Mechanism of Epilepsy

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