Lissencephaly refers to a rare condition in which the brain's typical folds do not develop, and brain development is disrupted. People with the condition often have intellectual disability and seizures. Although about twenty different genetic mutations that cause these conditions have been identified, no genetic cause has been found for some patients. Now, scientists have found a common biochemical mechanism underlying two genetically different lissencephaly disorders. These findings, which have been reported in Nature, have also identified a potential treatment for lissencephaly.
In this study, the investigators analyzed the genomes of lissencephaly patients, and revealed a novel gene linked to the disorder. This genetic mutation, and another mutation associated with liseencephaly was then modeled in cerebral organoids, which are miniature, simplified versions of human brains.
Lissencephaly patients not only have few folds in their brains, they also tend to have an unusually thick cerebral cortex layer. This thick cerebral cortex was also seen in the mutant brain organoids that were generated in this study, but not healthy control organoids.
The researchers determined that the mTOR pathway was also disrupted in both types of mutant organoids.
"This is a fundamental pathway that governs many different aspects of cellular metabolism to maintain cellular homeostasis," said co-senior study author Angeliki Louvi, professor of neurosurgery and of neuroscience at Yale School of Medicine (YSM). "And we know of many disorders in which the mTOR pathway is overactive, but here we found that in lissencephaly it's actually underperforming."
The mutant cerebral organoids were also exposed to a drug that increases the activity of the mTOR pathway, and the thickening in the cortical layer could be prevented, depending on when it the organoids were treated. This happened regardless of which lissencephaly-linked mutation was causing these symptoms.
Since this mechanism and the potential treatment were common to both mutations, this finding could also apply to lissencephaly that is caused by other mutations as well.
There is no treatment for these disorders right now, and clinicians have to treat symptoms. That can be challenging, however, because these disorders do not always respond to the anti-epileptic medications that are applied, explained lead study author Ce Zhang, MD, PhD.
"If there's a converging pathway shared between these disorders, regardless of the genetic cause, it could mean one treatment, such as an mTOR activator like the one we tested in the study might be beneficial to patients across the lissencephaly spectrum," said Zhang.
Now, more research will be needed to confirm and evaluate these findings in patients, and the researchers want to know more about what is going wrong with the mTOR pathway.
Sources: Yale University, Nature
