The role of ATP1A3 gene in epilepsy: We need to know more

Abstract

The ATP1A3 gene, which encodes the Na+/K+-ATPase α3 catalytic subunit, plays a crucial role in both physiological and pathological conditions in the brain, and mutations in this gene have been associated with a wide variety of neurological diseases by impacting the whole infant development stages. Cumulative clinical evidence suggests that some severe epileptic syndromes have been linked to mutations in ATP1A3, among which inactivating mutation of ATP1A3 has been intriguingly found to be a candidate pathogenesis for complex partial and generalized seizures, proposing ATP1A3 regulators as putative targets for the rational design of antiepileptic therapies. In this review, we introduced the physiological function of ATP1A3 and summarized the findings about ATP1A3 in epileptic conditions from both clinical and laboratory aspects at first. Then, some possible mechanisms of how ATP1A3 mutations result in epilepsy are provided. We think this review timely introduces the potential contribution of ATP1A3 mutations in both the genesis and progression of epilepsy. Taken that both the detailed mechanisms and therapeutic significance of ATP1A3 for epilepsy are not yet fully illustrated, we think that both in-depth mechanisms investigations and systematic intervention experiments targeting ATP1A3 are needed, and by doing so, perhaps a new light can be shed on treating ATP1A3-associated epilepsy.

Comparative analysis of hippocampal extracellular space uncovers widely altered peptidome upon epileptic seizure in urethane-anaesthetized rats

“…Four-AP induces extracellular K + accumulation in rat hippocampus [ 44 ]. Inactivating Atp1a3 mutation is associated with epileptic seizures since it increases the excitability of neurons [ 86 ]. We detected 8 increasing peptides of this protein in the microdialysate.…”

Clinical description and evaluation of 30 pediatric patients with ultra-rare diseases: A multicenter study with real-world data from Saudi Arabia

“…Additionally, an ATP1A3 variant have been associated with a spectrum of neurological disorders which includes alternating hemiplegia of childhood (AHC) and rapid-onset dystonia-parkinsonism (RDP) [ 40 ]. Interpreting ATP1A3 mutations involves assessing their impact on ion transport and neuronal excitability [ 41 ]. Mutations can disrupt the function of the Na+/K+-ATPase pump, leading to altered ion homeostasis and impaired neuronal signaling [ 41 ].…”

“…Interpreting ATP1A3 mutations involves assessing their impact on ion transport and neuronal excitability [ 41 ]. Mutations can disrupt the function of the Na+/K+-ATPase pump, leading to altered ion homeostasis and impaired neuronal signaling [ 41 ]. These disruptions can manifest as neurological symptoms, such as hemiplegia, dystonia, and parkinsonism [ 42 ].…”