Do you know: ‘Smooth brain’ disorders may have a common cause — and a possible treatment
in 2025
Lissencephaly is a spectrum of rare genetic disorders in which the brain fails to develop its characteristic folds. The disorders are often associated with seizures and intellectual disability and there is currently no treatment available.
However, a new Yale study has identified a molecular mechanism underlying some lissencephaly disorders – and a drug that prevents and reverses the malformation of lissencephaly in organisms (miniature three-dimensional replicas of a developing brain that allow scientists to study development early brain).
The results, reported January 1 i Natureit may target treatment, say researchers.
“Lissencephaly belongs to a group of disorders that we call cortical developmental malformations, which means that the normal development and structure of the brain is affected,” said Angeliki Louvi, professor of neurosurgery and neuroscience at the Yale School of Medicine (YSM) and common ancestor. author of the study. “They come about because rare mutations affect certain genes that are very important for brain development.”
The new study builds on gene discovery research by the Yale Program in Neurogenetics and co-senior author Murat Gunel, Sterling Professor of Neurosurgery and professor of genetics and neuroscience at YSM. For years, the program has collected blood samples from patients with brain malformations to identify genetic mutations associated with their disorders.
“It’s been 17 years since the first family enrolled in our research, and they happen to be one of the families in the study,” said Kaya Bilguvar, adjunct associate professor of neurosurgery and genetics at YSM, and co-senior author of part of the College. study. “This level of collective commitment, including patients and families, is encouraging.”
Past research has linked some genes to lissencephaly, but there are some cases of patients whose genetic causes are unknown. Furthermore, how these genetic mutations lead to lissencephaly at the molecular level is not well understood.
For the new study, the researchers discovered a new gene associated with lissencephaly and then developed brain organisms from the cells of patients with two different types of lissencephaly. Specifically, they took cells from strands of the patients’ hair and, through a chemical method, reversed the development of the cells, pushing them into an earlier unspecialized cell stage. The researchers then reprogrammed the cells to become neurons, which grew together to form three-dimensional organisms.
In addition to little or no folding in their brain, individuals with lissencephaly have a thicker cerebral cortex than normal. The organoids grown from the patients’ cells for the new study developed thicker cortex-like structures than healthy organisms, similar to what was observed in lissencephaly, researchers found.
The research team also performed a number of analyzes to assess gene and protein expression levels in the organisms. Their results showed dysregulation in the mTOR pathway (mammalian target of rapamycin) in both types of lissencephaly organisms they were studying.
“This is a fundamental pathway that regulates many different aspects of cellular metabolism to maintain cellular homeostasis,” Louvi said. “And we know many disorders in which the mTOR pathway is overactive, but here we discovered that in lissencephaly it is actually underperforming.”
Ultimately, the researchers exposed the organoids to a drug that promotes mTOR pathway activity and found that it could prevent and reverse the thickening of the organoid’s cortical plate-like area depending on when it was introduced.
“Currently, medically we have no way to slow down or reverse these structural brain malformations in lissencephaly during or after pregnancy,” said lead author Ce Zhang, who was an M.D.-Ph.D. . student in Bilguvar and Louvi’s labs and will soon begin a neuroscience residency at Ceders-Sinai in Los Angeles. “That limits us to treating the symptoms, but even that can be difficult, because lissencephaly seizures cannot be well controlled using standard anti-epileptic drugs.”
But since the study showed that the mTOR pathway is involved in two different types of lissencephaly, it suggests that this may be the case for additional types of lissencephaly – or perhaps even the entire spectrum of lissencephaly disorders.
“If there is a common pathway shared between these disorders, regardless of the genetic cause, it could mean that a single treatment, such as an mTOR activator like the one we tested in the study, could be beneficial for patients with across the lissencephaly spectrum,” Zhang said.
In the future, the researchers aim to determine if the mTOR pathway is involved in other genetic forms of lissencephaly and to dig deeper into how an inactive mTOR pathway leads to lissencephaly.
“These results add to our knowledge of this pathway, highlighting the fine balance that must be achieved for healthy brain development,” said Louvi. “Now we want to understand what happens molecularly when mTOR is underactivated.”
It will be important to explore potential clinical applications of mTOR activators in this spectrum of disorders as well, Bilguvar said, because it’s the patients who benefit while basic discoveries are the program’s ongoing motivation. .