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ATP1A3: A gene found to be responsible for early brain malformations

Recently, researchers have explored the pathophysiology of ATP1A3, a gene that encodes for an ATPase pump sub-unit in the brain.

Brain neurons transmit signals using a flow of Na+ and K+ ions. The integration of these signals from different cell types coordinates processes in the cerebral cortex, such as cell proliferation, migration, differentiation and maturation. An Na+/ K+ pump is required to maintain ionic gradients and cell membrane potentials in the brain. This pump is called Na+,K+ATPase and is powered by ATP hydrolysis.

A diagram showing the extrusion of 3 Na+ from the cell while 2 K+ entering the cell due to the activation of the Na+,K+ATPase enzyme. Image credit: Na+/K+‑pump and neurotransmitter membrane receptors. Arkady S. Pivovarov, 2018.

The Na+,K+ATPase protein complex contains a large alpha (α) sub-unit. A gene called ATP1A3 is particularly important for encoding this α sub-unit. Therefore, ATP1A3 is critical for several neurophysiological functions – most importantly the recovery of electrochemical gradients following signalling.

Mutations of the ATP1A3 gene have been associated with an assortment of neurological disorders, with onset ranging from the immediate postnatal period to adulthood. Some examples of these diseases include early infantile epileptic encephalopathy (EIEE), childhood onset schizophrenia and rapid-onset dystonia-parkinsonism (RDP). The broad spectrum of onset time suggests that vulnerability to ATP1A3 dysfunction may shift during different stages of brain maturation.

Studying ATP1A3

Recently, a team of researchers aimed to unravel the pathophysiology of ATP1A3 in the developing brain. They focussed mainly on prenatal and early childhood development. Four individuals who had polymicrogyria and novel ATP1A3 variants were studied. Polymicrogyria is a condition characterised by the abnormal development of the cerebral cortex before birth and is the most common brain malformation.

Over 125,000 individual cells from 11 areas of the human cerebral cortex were profiled. The scientists were able to identify key enrichments of ATP1A3 and describe the variants that encoded for dysfunctional α sub-units using single-cell approaches.

Some of the key findings were as follows:

  • Individuals with ATP1A3 variants displayed cortical malformation phenotypes.
  • Polymicrogyria-associated ATP1A3 mutations disrupted function.
  • ATP1A3 did not have higher prenatal expression than its paralogs and it persisted postnatally.
  • ATP1A3 was enriched with parvalbumin (PV) interneurons and excitatory neurons in infants.

Overall, the malformation phenotypes of affected individuals and patterns of ATP1A3 single-cell expression suggested a key role for the encoded α sub-unit. Therefore, the variable levels of α sub-unit between individuals may provide a partial explanation for the broad phenotypic ranges of diseases associated with specific ATP1A3 variants.

Prospect for ATP1A3-associated diseases

These findings have begun to uncover the cell-type basis for prenatal and early childhood ATP1A3-associated diseases. The novel insights into the molecular pathology of polymicrogyria provides a potential basis for an ATP1A3-related treatment.

Furthermore, the researchers compiled a single-cell atlas of ATP1A3 expression in the foetal and postnatal cerebral cortex. In the future, this spatiotemporal roadmap will offer endless opportunities for genotype-phenotype association studies that focus on Na+,K+ATPase α sub-unit function, ultimately driving the development of treatment options for ATP1A3-related diseases.

Image credit: FreePik ruslan ivantsov