HMN 2025: How ‘Smooth brain’ disorders may share a common cause and potential treatment

Lissencephaly is a spectrum of rare genetic disorders in which the brain fails to develop its characteristic folds. These disorders are often associated with seizures and intellectual disability and there is currently no treatment available.

A new Yale study, however, has identified a molecular mechanism that underlies some lissencephaly disorders and a drug that prevents and reverses lissencephaly malformations in organoids (small, three-dimensional replicas of the developing brain that allow scientists to study early brain development).

The findings, reported January 1 to Naturemay indicate a target for treatment, researchers say.

“Lissencephaly belongs to a group of disorders that we call malformations of cortical development, which means that normal development and structure of the brain are disrupted,” said Angeliki Louvi, professor of neurosurgery and neuroscience at the Yale School of Medicine. (YSM) and co-senior author of the study.

“They arise because certain genes that are very important for brain development are affected by rare mutations.”

The new study builds on gene discovery research led by the Yale Program in Neurogenetics and pioneered by 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 participating in the study,” said Kaya Bilguvar, associate professor of neurosurgery and genetics at the YSM and co-senior author of the study. study. “This level of collective commitment, including from patients and their families, is inspiring. »

Previous research has linked a number of genes to Ilsencephaly, but there are some cases of patients whose genetic causes remain unknown. Additionally, how these genetic mutations actually lead to Ilsencephaly at the molecular level has not been well understood.

For the new study, researchers discovered a new gene associated with Ilsencephaly, then grew brain organoids from the cells of patients with two different types of Ilsencephaly. Specifically, they took cells from strands of patients’ hair and, using a chemical method, reversed the development of the cells, pushing them to an earlier, unspecialized cell stage. The researchers then reprogrammed the cells to become neurons, which grew together to form three-dimensional organoids.

In addition to having little or no brain folding, people with lissencephaly also have a thicker cerebral cortex than usual. The organoids grown from the patients’ cells for the new study also developed thicker cortex-like structures than healthy organoids, much like what is seen in Ilsencephaly, the researchers found.

The research team also performed several analyzes to assess gene and protein expression levels in the organoids. Their results highlighted a deregulation of the mTOR pathway (mammalian target of rapamycin) in the two types of lissencephalic organoids they studied.

“This is a fundamental pathway that governs many aspects of cellular metabolism to maintain cellular homeostasis,” Louvi said. “And we know of many disorders in which the mTOR pathway is overactive, but we found here that in Ilsencephaly it’s actually underperforming.”

Ultimately, the researchers exposed the organoids to a drug that stimulates mTOR pathway activity and found that it could prevent and reverse thickening of the organoid cortical plate-like area depending on when he was introduced.

“Currently, in medicine, we have no way to slow down or reverse these structural brain malformations linked to Ilsencephaly, either during pregnancy or after,” said lead author Ce Zhang. , M.D. and Ph.D. student in the Bilguvar and Louvi labs and will soon begin his neurology residency at Cedars-Sinai in Los Angeles.

“This limits us to treating the symptoms, but even that can be difficult, because lissencephaly seizures may not be well controlled using conventional antiepileptic medications.”

But since the study showed that the mTOR pathway is involved in two different types of Ilsencephaly, it suggests that this could be the case for other types of Ilsencephaly – or perhaps even for the entire spectrum of disorders. lissencephaly.

“If there is a shared convergent pathway between these disorders, regardless of the genetic cause, this could mean that a treatment, such as an mTOR activator like the one we tested in the study, could be beneficial for patients across the spectrum of Ilsencephaly,” Zhang said. .

In the future, researchers aim to determine whether the mTOR pathway is involved in other genetic types of Ilsencephaly and to delve further into how an underactive mTOR pathway leads to Ilsencephaly.

“These results expand our knowledge of this pathway, highlighting the delicate balance that must be achieved for healthy brain development,” Louvi said. “We now want to understand what exactly happens at the molecular level when mTOR is underactivated.”

It will also be important to explore potential clinical applications of mTOR activators across this spectrum of disorders, Bilguvar added, as they will benefit patients, although fundamental discoveries provide the program’s continued motivation.