Michel Cayouette and his team are looking at whether the loss of cellular polarity could be a mechanism underlying multiple brain diseases, such as neurodegenerative diseases (like Alzheimer’s disease, stroke, and retinal degeneration), neuronal connectivity diseases (such as autism and schizophrenia), and brain cancer. Cell polarity is what gives neuronal cells their unique shape (cell morphology) that is essential to perform their function. Just like there are hundreds of different shapes of leafs in nature, there are hundreds of different neuronal cell morphologies. Dr. Cayouette’s team is trying to figure out how each cell is shaped, as this is essential information not only to understand how the shape of each cell affects brain function, but also because it is one of the first features that goes wrong in disease. They know that the key to cell polarity processes are PAR proteins, a family of proteins responsible for correctly segregating cellular components.

In their project, they propose to use innovative molecular and cellular approaches to investigate the role of these proteins in four critical neuronal events underlying multiple brain diseases. These studies are having a major impact on the fundamental understanding of cell polarity and have the potential to determine a common underlying cause of neuronal disruption and discover new treatments for a wide spectrum of neurological diseases.

Image of a zebrafish brain.

Image of a zebrafish brain.

Over the past three years of the grant, the team has made important advances in their understanding of neurodevelopmental and neurodegenerative disorders. They have uncovered genetic pathways essential for neuronal development, the formation of neuronal circuits, and the survival of neurons, paving the way to identification of new therapeutic targets for neurodegenerative diseases. They have also identified a novel regulator controlling the levels of toxic proteins that accumulate in Alzheimer’s disease, offering a novel avenue for therapeutic intervention. This work has major implications for understanding how local neural circuit environments are altered in brain diseases such as epilepsy, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.

The next steps will be to use the fundamental knowledge that they have generated to develop novel therapeutic interventions. The team is eager to test whether the new protein they identified can be used to stimulate the removal of toxic proteins in neurons in pre-clinical models of Alzheimer’s disease, which will be a first step towards developing drug targets in humans. Additionally, their studies have identified potential biomarkers for brain cancers, and uncovered new mechanisms by which neuronal activity can be altered during disease, which could be exploited to treat various neurological disorders.

“This grant allowed us to establish strong ties between our different research teams that are continuing to this day to develop new projects and collaborations.”

— Michel Cayouette, Ph.D. Montreal Clinical Research Institute