Non-histone substrates of histone deacetylases as potential therapeutic targets in epilepsy

ABSTRACT

Introduction: Epilepsy is a network-level neurological disorder characterized by unprovoked recurrent seizures and associated comorbidities. Aberrant activity and localization of histone deacetylases (HDACs) have been reported in epilepsy and HDAC inhibitors (HDACi) have been used for therapeutic purposes. Several non-histone targets of HDACs have been recognized whose reversible acetylation can modulate protein functions and can contribute to disease pathology.

Areas covered: This review provides an overview of HDACs in epilepsy and reflects its action on non-histone substrates involved in the pathogenesis of epilepsy and explores the effectiveness of HDACi as anti-epileptic drugs (AEDs). It also covers the efforts undertaken to target the interaction of HDACs with their substrates. We have further discussed non-deacetylase activity possessed by specific HDACs that might be essential in unraveling the molecular mechanism underlying the disease. For this purpose, relevant literature from 1996 to 2020 was derived from PubMed.

Expert opinion: The interaction of HDACs and their non-histone substrates can serve as a promising therapeutic target for epilepsy. Pan-HDACi offers limited benefits to the epileptic patients. Thus, identification of novel targets of HDACs contributing to the disease and designing inhibitors targeting these complexes would be more effective and holds a greater potential as an anti-epileptogenic therapy.

KEYWORDS:

• Antiepileptic drugs
• epilepsy
• epileptogenesis
• histone deacetylase (HDAC)
• HDAC inhibitor
• seizure

Article highlights

• HDACs beyond deacetylating histone proteins also deacetylate non-histone proteins and regulate several neurobiological processes.

• HDACs act as a double-edged sword by exerting both neuroprotective and neurotoxic roles, depending on its subcellular localization, post-translational modifications, and its interacting proteins.

• Aberrant deacetylation of non-histone proteins is responsible for dysregulated neurogenesis, oxidative stress, synapse remodeling, inflammation, neural changes, altered signaling pathways, etc. that are hallmarks of epileptogenesis.

• HDACs 4 and 7 are also reported to have sumoylation activity and one of the sumoylating effects of HDAC4 is the prevention of neuroinflammation via modulating Liver X receptor alpha and beta activity (LXR-α and LXR-β)

• HDAC6 is also found to have Ubiquitin-dependent function, where it modulates protein degradation and regulates cytotoxic protein aggregation.

• Identification of HDACs and their interacting non-histone substrates that contribute to the pathology of the disease can serve as novel therapeutic targets for epilepsy.

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Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This article is funded by the Department of Biotechnology, Ministry of Science and Technology [BT/MED/122/SP2A580/2018].