A new study by the University of Campinas (UNICAMP) in Brazil suggests that dysregulation in the expression of NEUROG2, a gene involved in the differentiation of neurons and glial cells, plays a key role in the development of epilepsy

"We show that expression of the microRNA hsa-miR-34a is reduced in the brain tissue of patients with focal cortical dysplasia and that this appears to result in overexpression of NEUROG2. We believe this factor may be associated with nerve cell differentiation failure," said Iscia Lopes-Cendes, a professor in UNICAMP's Medical School and supervisor of the research project. 

"Our findings are based on analysis of the brain tissue of 16 patients with type II focal cortical dysplasia, a malformation with cortical disorganization and aberrant nerve cells including dysmorphic neurons that are constantly in a state of excitation and hence favor epileptic seizures," Cendes explained.

According to Cendes, some 25% of patients with refractory epilepsy requiring surgery have focal cortical dysplasia. The proportion is much higher among children, however. Indeed, cortical malformation is the main cause of intractable epilepsy in children.

Previous research associated the appearance of focal cortical dysplasia with mutations in a cell signaling pathway mediated by the protein mTOR. Hyperactive mTOR signaling leads to abnormal cell proliferation. However, these somatic mutations have been found in roughly a quarter of those affected by the disease and hence cannot explain all cases of cortical malformation.

Regulation by microRNA

The researchers decided to look for other possible causes of cortical malformation by analyzing microRNA expression in tissue taken from patients treated at UNICAMP's general and teaching hospital. MicroRNAs are small RNA molecules that do not contain information for protein synthesis but are capable of binding to protein-encoding genes and modulating their expression.

"We observed a difference in the expression of only three microRNAs: hsa-let-7f, hsa-miR-31, and hsa-miR-34. We then used bioinformatics to see which genes these molecules might be interacting with and arrived at a list of ten candidates," Cendes said.

"By binding to genes, microRNAs inhibit their expression, so when a microRNA is underexpressed the gene becomes more active. This is a kind of reverse regulation. Because NEUROG2 appears to be an important gene for brain development, we decided to investigate further," Cendes said.

The group then performed binding assays to prove that increased expression of this gene was linked to the reduction in hsa-miR-34a. The results showed that the microRNA is capable of binding to an important region of NEUROG2 and inhibiting its activity.

"We decided to investigate in more depth and showed that in the tissue of patients with dysplasia the gene RND2—which is regulated by NEUROG2 and associated with the same signaling pathway—was also overexpressed. This was not observed in the control tissue," Cendes said.

"We believe that when NEUROG2 has overexpressed this transition from neurogenesis to gliogenesis doesn't take place adequately because the signal that stimulates neurogenesis remains active when it should become inactive. This dysregulation stays in dysplastic tissue from embryonic development until adulthood," she said.

"It's possible that dysregulation of hsa-miR-34 is linked to an environmental factor such as a viral infection during pregnancy, for example. These are hypotheses that will have to be tested in future research," she said.