Blocking Activity of α1-NaKA Can Restore Certain Neurological Deficits in Angelman, Mouse Study Suggests

Blocking the activity of sodium-potassium ATPase, an enzyme that is essential in maintaining ion balance in all types of cells, can restore calcium dynamics and other abnormal neurological features in a mouse model of Angelman syndrome (AS), a study has found.

The study, “α1-Na/K-ATPase inhibition rescues aberrant dendritic calcium dynamics and memory deficits in the hippocampus of an Angelman syndrome mouse model,” was published in Progress in Neurobiology.

Angelman syndrome is a genetic neurological disorder caused by the loss or malfunction of the maternal copy of the UBE3A gene in neurons from specific regions of the brain. This gene provides instructions to make an enzyme called ubiquitin protein ligase E3A, which normally targets other proteins to be destroyed.

Previous preclinical studies have shown that the alpha-1-sodium-potassium ATPase (α1-Na/K-ATPase, or α1-NaKA), one of the two main forms of Na/K-ATPase, is produced at high levels in the hippocampus — a brain region involved in short-term memory — of two-week-old mice with Angelman syndrome.

Na/K-ATPase is a molecule that plays a critical role in maintaining cell volume and several of the cell’s key properties. It also modulates calcium dynamics (the entry and exit of calcium) within cells by controlling the flux of sodium gradients.

Calcium is constantly entering and leaving cells, a physiological phenomenon that regulates several cellular functions, such as enzyme activation, muscle contraction, cell differentiation, and gene activation. Calcium dynamics also regulate many neurological functions, including synapses — the junctions between two nerve cells that allow them to communicate — and synaptic plasticity, or the ability of synapses to strengthen or weaken over time.

Previous research has shown that genetically reducing the production of α1-NaKA in adult mice prevents them from developing memory deficits and defects in synaptic plasticity associated with Angelman.

“[T]hese findings suggest that increased α1-NaKA expression in the AS hippocampus is the precipitating event for AS hippocampal deficits,” the investigators said.

In this study, researchers from the Integrated Brain and Behavior Research Center at the University of Haifa, in Israel, set out to explore the mechanisms by which high levels of α1-NaKA negatively impact the hippocampus in a mouse model of Angelman syndrome.

They found that in adult mice with Angelman, the activity of α1-NaKA was abnormally high compared to healthy animals, which was reflected by abnormal calcium dynamics in their hippocampus.

However, when these animals were treated with marinobufagenin, a selective pharmacological inhibitor of α1-NaKA, calcium dynamics normalized in their hippocampus.

Moreover, the researchers found that blocking the activity of α1-NaKA with a pharmacological inhibitor also restored synaptic plasticity and reverted cognitive impairments associated with hippocampus malfunction, including memory and learning deficits, in sick animals.

“Altogether, our study implicates the modification of Ca²⁺ [calcium] dynamics as one of the major underlying mechanisms by which enhanced α1-NaKA expression induces deleterious [negative] effects in the hippocampus of AS model mice,” the researchers wrote.

“Furthermore, we propose that selectively modulating NaKA isoforms might carry therapeutic significance even in adult AS mice, when genetic intervention therapies are not always successful,” they added.