m6A methylation: a new frontier in epilepsy research and therapeutics

Abstract

Epilepsy is a highly complex and global neurological disorder, for which available treatments only inadequately control the disease in many patients. Recent advances in molecular research have identified N6-methyladenosine (m6A) RNA modifications as key regulators of neuronal processes that underpin the pathophysiology of epilepsy. This review critically discusses the emerging significance of m6A modifications in epilepsy, focusing on dynamic regulations of m6A "writers," "erasers," and "readers" for modulating gene expression, neuronal excitability, and synaptic plasticity in epilepsy. Dysregulation of m6A machinery promotes epilepsy by exacerbating oxidative stress, mitochondrial dysfunction, and neuronal damage. We also discuss the prognostic significance of m6A alterations as a potential biomarker in epilepsy diagnosis and disease progression, along with advanced therapeutic strategies against m6A, including small molecules, RNA editing technologies, and precision medicine. This review highlights the transformational significance of m6A modulation in epilepsy therapy and opens new avenues for personalized therapeutic strategies that may revolutionize the field of drug-resistant epilepsy and improve the prognosis for patients. See also the graphical abstract(Fig. 1).

Keywords: epilepsy; m6A modification; m6A regulators; molecular biomarkers; neurodegeneration; precision medicine.

Figure 1. Graphical abstract

Figure 2. Current epilepsy treatment options

Figure 3. Overview of the mechanisms of modification of m6A, highlighting writers, erasers, and readers along with their roles in RNA regulation

Figure 4. Schematic representation of the integration between extrinsic signaling pathways (e.g., NF-κB, mTORC1, and Wnt/β-catenin) and the m6A RNA modification machinery. External cues such as stress, cytokines, and nutrients activate intracellular pathways that regulate the expression or activity of m6A writers, erasers, and readers. These modifications influence RNA fate, stability, degradation, or translation, ultimately affecting gene expression involved in inflammation, regeneration, and tumorigenesis.

Figure 5. Physiological roles of m6A modification in neuronal function

Figure 6. Role of the methyltransferase complex (MTC) in m6a modification and neurological disorders. This diagram illustrates the formation of the MTC and its key components, which contribute to m6A RNA modification through functions such as target identification, stability enhancement, functionality support, and RNA binding. The m6A modification subsequently influences gene activity regulation, impacting neurological processes that may lead to conditions like neuron deterioration, AD, PD, and epilepsy.