Polymicrogyria is a very rare neurological disease caused by a brain malformation. Affected children have a cerebral cortex with many more folds than normal, leading to severe developmental delay, intellectual disability, and epilepsy. This overfolding condition of the brain is caused by mutations in several genes , one of which has been found to be crucial in the developing brain.
We are talking about ATP1A3, a gene that encodes a protein that is part of the sodium potassium cell pump , responsible for moving these ions through the cell membrane. In this way, cells maintain concentrations of charged ions on both sides of the membrane, functioning in a similar way to a battery, since these differences allow electrical currents to enter or leave the cells, driving action potentials in neurons and enabling essential cellular functions.
Bioelectricity and brain development
A team from Children’s Hospital Boston has been studying the genes involved in the appearance of polymicrogyria, and thanks to this analysis the researchers have described the essential role of the ATP1A3 gene: ” It is one of the most important genes that we have in our brain, and fundamental for many cellular biological processes “, explains Richard Smith, one of the authors of the work.
The scientists analyzed donated human tissue samples from various tissue banks and analyzed them at two stages of early brain development: around 20 weeks’ gestation, at which point the initially smooth fetal cortex begins to fold, and in infants shortly after birth.
Using single cell RNA sequencing (DropSeq) they looked for expression of ATP1A3 in approximately 125,000 individual neurons from eleven areas of the prenatal cortex. They also profiled about 52,000 neurons from the babies, sampling four areas of the cortex.
In general, ATP1A3 expression levels were highest in the prefrontal cortex at both time points, and highest in the most active and frequently activated neurons of the cortex. In the fetal cortex, ATP1A3 expression was particularly high in the subplate, a layer that disappears later in development. The electrical activity in the subplate is believed to be a signaling center that drives synapse formation, neuron migration, and other brain development processes.
“In babies, we found increased expression of the gene in interneurons, which are inhibitory,” explains Smith. “We believe that ATP1A3 mutations can alter the balance of excitation and inhibition in the brain, which could contribute to epilepsy in other ATP1A3-related conditions.”
The work, which is published in the journal PNAS , highlights the importance of the study of rare diseases because, in addition to helping people who suffer from them, they can contribute to producing fundamental knowledge in the field of biology, in this case , helping to understand how the brain develops its contours and its organizational pattern from a very early age.
The findings may also inform scientists about understanding other known ATP1A3-related disorders. While polymicrogyria patients had severe mutations that caused loss of gene function, milder mutations cause a spectrum of late-onset neurological diseases, including childhood alternate hemiplegia, which causes episodes of temporary paralysis; a movement disorder known as rapid-onset dystonia parkinsonism; and childhood-onset schizophrenia. These late-onset disorders may be more amenable to therapeutic intervention.
“Polymicrogyria is at the extreme of severity, but we believe that ATP1A3-related disorders in the ‘middle’ of this spectrum could have early pathogenic roots that could possibly be treated before they become more severe,” says Smith.
He adds that if newborn DNA sequencing becomes common, it could offer a window of opportunity to treat ATP1A3-related disorders before they become clinically manifest.
As for polymicrogyria, “a structural malformation is more difficult to reverse, but baby brains are incredibly plastic and capable of reorganization,” says Smith. “If the damage related to early epilepsy could be reduced, the quality of life for these children could be improved .”
