Molecules with anti-inflammatory, restorative properties could be key to tackling neurodegenerative disease

Aalyssa Atley • Posted: April 5, 2022

GlycoNet researchers at the University of Alberta are studying a group of molecules that could provide insight into treating and monitoring neurodegenerative diseases.

GlycoNet researcher Simonetta Sipione is a professor at the University of Alberta. (Photo: GlycoNet)

GlycoNet researchers have found that gangliosides, a family of molecules with carbohydrate and lipid properties, provide protective effects against neurodegenerative disease and could lead to development of a potential treatment. They are also investigating whether gangliosides could be valuable indicators, or biomarkers, of neurodegeneration.

Simonetta Sipione, a GlycoNet researcher and professor in the University of Alberta’s Faculty of Medicine and Dentistry, has been leading research on the role of gangliosides in the brain, using cell and mouse models of Huntington’s disease—a rare genetic neurodegenerative disorder that shares characteristics with more common neurodegenerative diseases including Alzheimer’s and Parkinson’s.

Gangliosides are abundant in the brain and are important for brain health. When Sipione and her team discovered that the production of gangliosides was impaired in Huntington’s disease, they wondered whether boosting ganglioside levels could stop neurodegeneration. The researchers increased the levels of a particular ganglioside called GM1 in the brains of Huntington’s mice, and found GM1 was able to block neurodegeneration and restore normal behaviour.

“When we gave GM1 to these mice, we were able to restore motor function to normal, reduce depression and anxiety, and improve cognition,” says Sipione. “We were able to improve all disease symptoms.”

In a paper recently published in the Journal of Neuroinflammation, Sipione and her team found that GM1 decreases inflammatory responses by the immune cells of the brain, called microglia. Meanwhile, a lower amount of gangliosides in microglia was associated with increased inflammatory response. This observation could mean that changes in gangliosides contribute to making microglia more or less prone to inflammation.

“This is important because brain inflammation, known as neuroinflammation, has been described as a contributor to disease progression in Huntington’s disease,” explains Sipione. “Neuroinflammation also occurs in other diseases like Alzheimer’s or Parkinson’s disease.”

Another protective mechanism the research team is studying is the ability of GM1 and other gangliosides to promote cellular secretion of toxic proteins that contribute to disease, packed into nanoparticles called extracellular vesicles. These extracellular vesicles play a role in cell communication and help regulate the immune system. Sipione suspects that GM1 and other gangliosides improve the packaging and disposal of toxic proteins as part of the brain’s “trash collection” process. Microglia can then eliminate, at least in part, these extracellular vesicles and the toxic proteins they carry.

In collaboration with GlycoNet researchers John Klassen et Matthew Macauley at the U of A, Sipione is investigating the mechanisms of gangliosides to better understand their protective effects, which will inform the development of a possible treatment for Huntington’s and potentially other neurodegenerative diseases.

Potential biomarkers of neurodegenerative disease progression

Working with Klassen and U of A neurologist Oksana Suchowersky, Sipione is looking at how the levels of gangliosides in cerebrospinal fluid (surrounding the brain and spinal cord) correlate with disease progression or the severity of symptoms.

Through a partnership with HDClarity, a cerebrospinal fluid collection initiative, the research team is analyzing human cerebrospinal fluid samples taken from both Huntington’s disease patients and healthy individuals. Once the team compiles the data on the levels of gangliosides, they will use machine learning tools to establish whether there are specific correlations between the level of one or more gangliosides and disease severity.

“There are very few biomarkers of neurodegeneration and disease progression that are easy to measure in Huntington’s disease patients,” says Sipione. “If we find that the levels of gangliosides correlate with disease severity, then we could measure the levels of gangliosides to predict disease progression in patients, and to predict or evaluate the effectiveness of potential treatments in clinical trials.”

The research has received funding from GlycoNet, Canadian Institutes of Health Research (CIHR), and the University Hospital Foundation.

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