U of T researchers' approach to producing neural cells could yield new treatments for Parkinson’s

An antibody was used to selectively activate a receptor in a molecular signalling pathway to develop dopaminergic neurons

PhD Student Andy Yang, left, and Professor Stephane Angers, right, at the Donnelly Centre for Cellular and Molecular Biology are advancing a novel approach to developing dopaminergic neurons (supplied images)

Researchers at the University of Toronto believe they’ve found a way to better control the generation of key neurons depleted in Parkinson’s disease – suggesting a potentially new approach to addressing a disease with no cure and few effective treatments.

In preclinical studies, the researchers used an antibody to selectively activate a receptor in a molecular signalling pathway to develop dopaminergic neurons. These neurons produce dopamine, a neurotransmitter critical to brain health.

While researchers around the world have been working to coax stem cells to differentiate into dopaminergic neurons to replace those lost in patients living with Parkinson’s disease, the efforts have so far been hindered in part by an inability to target specific receptors and areas of the brain.

“We used synthetic antibodies that we had previously developed to target the Wnt signaling pathway,” said principal investigator Stephane Angers, who is director of U of T’s Donnelly Centre for Cellular and Molecular Biology and a professor in the Leslie Dan Faculty of Pharmacy and the Temerty Faculty of Medicine.

“We can selectively activate this pathway to direct stem cells in the midbrain to develop into neurons by targeting specific receptors in the pathway. This activation method has not been explored before.”

Parkinson’s disease is the second-most common neurological disorder after Alzheimer’s, affecting over 100,000 Canadians. It particularly impacts older men, progressively impairing movement and causing pain as well as sleep and mental health issues.

Most previous research efforts to activate the Wnt signaling pathway relied on a GSK3 enzyme inhibitor. This method involves multiple signaling pathways for stem cell proliferation and differentiation, which can have an unintended effect on the newly produced neurons and activate off-target cells.

“We developed an efficient method for stimulating stem cell differentiation to produce neural cells in the midbrain,” said Andy Yang, first author on the study and a PhD student at the Donnelly Centre. “Moreover, cells activated via the FZD5 receptor closely resemble dopaminergic neurons of natural origin.”

Another promising finding of the study, published recently in the journal Development, is that implanting the artificially-produced neurons in a rodent model with Parkinson’s disease led to improvement of the rodent’s locomotive impairment.

“Our next step would be to continue using rodent or other suitable models to compare the outcomes of activating the FZD5 receptor and inhibiting GSK3,” said Yang. “These experiments will confirm which method is more effective in improving symptoms of Parkinson’s disease ahead of clinical trials.”

The research was supported by U of T’s Medicine by Design program, an institutional strategic initiative that receives funding from the Canada First Research Excellence Fund and the Canadian Institutes of Health Research.