A University of Alberta research team has discovered a new function for brain molecules known as gangliosides, offering potential new targets for the treatment of Huntington's and other genetic neurological diseases.
In their paper published in Science Advances, the team shows that gangliosides are key to the formation and release of extracellular vesicles, tiny particles that are responsible for both cell communication and cell waste disposal.
"Our recent study has uncovered a quite unexpected role for these fascinating molecules that are half fat and half sugar," says principal investigator Simonetta Sipione, professor of pharmacology and a member of the Canadian Glycomics Network, the Neuroscience and Mental Health Institute and the Glycomics Institute of Alberta. "This is something that contributes to disease pathogenesis and can be a target for therapeutic intervention."
Earlier research by Sipione's lab already showed that low levels of gangliosides were associated with Huntington's symptoms, but they weren't quite sure what role the molecules played in the disease. The team had also found that by restoring one particular ganglioside called GM1, they could reverse Huntington's symptoms in mice.
One in every 7,000 Canadians has Huntington's, a genetic brain disorder with physical, mental and emotional symptoms, according to the Brain Canada Foundation. It occurs when mutant huntingtin protein misfolds and clumps inside brain cells, causing them to malfunction and eventually die.
"Now we know that when gangliosides are low — not just in Huntington's disease but also in Parkinson's and in other hereditary neurodegenerative diseases — the vesicle-mediated cell communication and clearance system doesn't work properly," says Sipione. "This allows harmful proteins such as mutant huntingtin to accumulate and thus contributes to the processes that drive neurodegeneration."
Sipione will continue research to fully understand the underlying mechanisms of gangliosides to determine their clinical potential.
"We are still working to understand the full picture of how gangliosides protect the brain and how they might be used as restorative therapies in neurodegenerative diseases," says Sipione, who is collaborating with a biotech company to explore the possibility of future clinical trials. While gangliosides can be synthesized or extracted from the brains of other animals that have been used for meat consumption, and they have been used as therapeutic agents for other conditions, they are not approved for use in North America.
One hurdle is that when gangliosides are injected into the blood, very little makes it into the brain because of a protective feature known as the blood-brain barrier. It is still uncertain whether this limited amount is sufficient to have therapeutic effects. Sipione says alternative delivery methods such as nanoparticles, a nasal spray or a spinal injection might be needed to ensure effective delivery to the brain.
Sipione credits "outstanding" graduate students and first authors John Monyror and Vaibhavi Kadam for their experimental work, as well as the collaboration of pharmacology professor and co-corresponding author Elena Posse de Chaves and colleagues in the Faculty of Medicine & Dentistry.
Some of this research was carried out at the U of A's Flow Cytometry Facility. It was funded by the Canadian Institutes of Health Research, the Canadian Glycomics Network, the Brain Canada Foundation, the Natural Sciences and Engineering Council of Canada, the Huntington Society of Canada and the Alberta Prion Research Institute.
"It's the commitment of these partner funding agencies to fundamental neuroscience research that makes discoveries like this, with the potential to one day translate into new treatments, possible," Sipione says.
