GlycoNet researchers are working on ways to slow down neural cell death
By Ali Chou
Neurodegenerative diseases like Alzheimer’s, Parkinson’s, or Huntington’s diseases are leading causes of death and disability in Canada, especially in people over the age of 65. These diseases impact not just patients, but entire families and communities. Over 747,000 Canadians suffer from Alzheimer’s disease, Parkinson’s disease, or others that cause dementia. About 1 in every 7,000 people are affected by Huntington disease. As Canada’s population continues to age, it is assumed that the number of people affected by one of these illnesses will increase. This makes finding treatments and gaining better understanding of the progression of neurodegenerative diseases more important than ever.
GlycoNet researchers Drs. Simonetta Sipione, Matthew Macauley, and John Klassen from the University of Alberta are on the case. They have been making significant strides in identifying the culprit proteins that trigger neurodegenerative diseases. They are now searching for ways to block these triggers.
“The triggers to various neurodegenerative disorders may be different, but they all lead to similar consequences – misfolded proteins accumulating in the brain, causing neural cell death,” says Sipione. “We are trying to find methods to prevent the accumulation of these proteins.”
Sipione discovered that GM1, a glycolipid normally abundant in healthy brains, plays a crucial role in neurodegenerative diseases. It might also provide clues to effective therapeutic avenues.
“We found that patients with Huntington’s disease have partially decreased level of GM1 on the surface of their brain cells,” says Sipione. “And this slight change in the amount of GM1 cascades to serious consequences—brain cells become more vulnerable to toxins in the environment and to changes in the concentration of regulatory molecules for cell function and survival. But when we administered GM1 into mouse models of the disease, the results showed that disease symptoms are greatly attenuated and disease progression slows down. There is less inflammation in the brain, and the accumulation of misfolded proteins decreases.”
The discovery of the positive effect of GM1 on this neurodegenerative disease is a huge step towards its application as a therapeutic agent, not just in Huntington’s disease, but potentially also in Parkinson’s and other similar diseases. But for it to reach the clinic, there is more to be investigated into.
“It is still unclear what the mechanism of action of GM1 is, and if GM1 could reach the brain, or how much GM1 could reach the brain, if given by injection. One of our next steps is to investigate different routes of administration in order to maximize the effect of GM1,” says Sipione.
Sipione emphasizes that while substantial efforts are being made to move GM1 to clinical research, the determinant for the project success is the collaborations with Klassen and Macauley. The tools and expertise from these Investigators are helping Sipione’s team gain a better understanding of the mechanism of GM1 in the brain.
In particular, Klassen’s group is using mass spectrometry to monitor where GM1 is traveling when administered through various routes (e.g. with an injection or through nasal spray). This may help determine which administration path is the most effective. The team is also looking at possible molecules GM1 interacts with to mediate its therapeutic effect. On the other hand, Macauley’s lab is exploring the interactions between GM1 and a group of carbohydrate-binding proteins called “siglecs” to figure out how GM1 reduces inflammation in the brain.
“It’s always challenging to embrace a problem from aspects outside your expertise,” says Sipione. “However, like piecing together a puzzle, when working in a collaborative setting, the strengths of one team build on top of another and eventually form a 360o view to tackle the problem.”
Although still at an early stage, Sipione says the team may be on the right track to identify several key proteins that interact with GM1 to mediate some of its protective effects. The researchers hope to use this knowledge not only to better understand the mechanism of GM1 inside the brain, but also to give insight into the development of therapeutics for neurodegenerative diseases.