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

Abstract

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.

Altered Proteins in the Hippocampus of Patients with Mesial Temporal Lobe Epilepsy

“…Most of these proteins do not have a well-defined role in the epileptic process. Epilepsy is often associated with defects in ion channel proteins [31]. The fact that we did not find alterations in ion channel proteins may be explained by specific features of MTLE or by the insufficient amounts of samples that we have analyzed.…”

Hippocampal Proteome of Rats Subjected to the Li-Pilocarpine Epilepsy Model and the Effect of Carisbamate Treatment

“…Different neurodegenerative diseases show alterations in this protein [ 48 , 49 ]. This protein is able to form pores on ion channels in the membrane with direct consequence on conductivity [ 50 ]. An important role for this protein has been suggested in maintenance of the supply of synaptic vesicles in presynaptic terminals [ 51 ].…”

ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives

“…A growing number of recent findings point to an important role of epigenetic mechanisms associated with several human diseases (Surguchov et al, 2017). In this context, several authors highlighted the regulatory role of 17β-estradiol (E 2 ), a primary female sex steroid, in the expression of ACE2 in a tissuedependent fashion.…”