Study opens new frontier for research into neurodevelopmental disorder

Better healthcare
Faculty of Medicine
Research and innovation

By David McFadden

Research Writer, University of Ottawa

Neurons in the brain
The new research from the Faculty of Medicine could pave a way for pharmacological interventions for a devastating brain abnormality.

An international team led by a newly appointed Canada Research Chair at the uOttawa Faculty of Medicine has shed light on the underlying mechanisms of a mysterious brain abnormality that occurs during human fetal development.

By uncovering these hidden mechanisms, scientists could potentially design new strategies to better understand “Periventricular heterotopia” (PH) and prompt bench-to-bedside translation from the laboratory into the clinic to efficiently treat this devastating disorder.

PH is a neurodevelopmental affliction that’s characterized by an abnormal migration of neuronal cells. These cells end up clustering around ventricles, the cavities of the brain. The disorder typically becomes apparent with recurrent seizures. It is genetically heterogenous, meaning that mutations in distinct genes may lead to PH.

The collaborative research team led by uOttawa’s Dr. Armen Saghatelyan aimed to uncover the migratory mechanisms of grafted human neuronal progenitor cells derived from PH patients in the brains of an immunodeficient mouse model. They wanted to test the hypothesis that changes in autophagy – a kind of cellular recycling process in which a cell turns on itself to discard unwanted material – impact the neuronal cells’ abnormal migratory behaviours.

Dr. Armen Saghatelyan

“We hope that our findings may pave a way for pharmacological intervention in PH patients to counteract the migratory deficits of neuronal cells induced by PH-inducing genetic mutations.”

Dr. Armen Saghatelyan

— Canada Research Chair in postnatal neurogenesis

What they discovered was highly compelling. With rigorous experiments using the FDA-approved drug metformin to modulate autophagy, the team were ultimately able to restore the migratory properties of neuronal cells derived from PH patients. In a nutshell, the team found the drug restored the cells’ migratory properties by triggering autophagy.

Metformin is a commonly prescribed drug. The oral medication was introduced decades ago and is a first-line treatment for Type 2 diabetes, helping people improve their blood-sugar control and sensitivity to insulin.

“Since metformin is already used for the treatment of diabetes and in pediatric clinical trials, our results open up the possibility of pharmacological interventions in PH patients to counteract, at least partially, the migratory deficits of neuronal cells causing a critical malformation,” says Dr. Saghatelyan, who was recently named Canada Research Chair in postnatal neurogenesis and is a professor in the Department of Cellular and Molecular Medicine.

“We hope that our findings may pave a way for pharmacological intervention in PH patients to counteract the migratory deficits of neuronal cells induced by PH-inducing genetic mutations.”

Prior to this study, the underlying mechanisms of PH neuronal cell migration was unknown. It was also totally unclear whether migratory deficits might be restored by modulating other pathways not affected by the genetic mutations.

The team’s findings were published recently in the journal EMBO Molecular Medicine. It was supported by a CIHR operating grant to Dr. Saghatelyan’s lab.

Dr. Saghatelyan served as the study’s senior author. Cedric Bressan, a PhD student in his lab, is the first author. Dr. Saghatelyan says the core component of the research was the development of strategies to transplant human neuronal cells into the brains of immunodeficient mice and using various live imaging approaches to monitor their dynamics and migratory characteristics. This work started eight years ago, first in his lab at Université Laval, and later at his lab at uOttawa.

Additional groups involved in this work were laboratories of Dr. Stephen Robertson, of the University of Otego in New Zealand; Dr. Silvia Cappello, at the Max Planck Institute of Psychiatry in Germany; and Dr. Martin Parent, at the Université Laval.

What’s next for the research team? They are currently working with clinicians to interrogate clinical datasets and assess if there are cases when metformin has been given to mothers of PH patients during their pregnancy to treat pregnancy-induced diabetes. And if so, they seek to figure out how it impacted the migration of neuronal progenitors and their accumulation around the ventricles.

“The details could have a direct impact on the development of new strategies for the treatment of this disorder and highly accelerate the transition for clinical trials to cure PH,” Dr. Saghatelyan says.

'Metformin rescues migratory deficits of cells derived from patients with periventricular heterotopia' is published in EMBO Molecular Medicine on August 23, 2023. DOI: 10.15252/emmm.202216908

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