Measuring and increasing enzyme activity may hold the key to treating Parkinson’s disease

While the causes of Parkinson’s disease are not yet fully understood, recent research has pointed to a mutant gene with a link to carbohydrates, and this has drawn the attention of GlycoNet investigators.

Dr. David Vocadlo (Simon Fraser University) and his colleagues from across the country are currently working on a project that aims to treat this mutant gene, called GBA, which has now been identified as the greatest genetic risk factor for the development of Parkinson’s.

“If you don’t have two functional copies of this gene you’re at a dramatically increased risk of Parkinson’s, and that’s true of populations around the world,” says Vocadlo. The mutant gene causes a decreased level of an enzyme called glucocerebrosidase, which cuts sugars from certain lipids, allowing these brain lipids to break down.

“We recognized that what one would want to do is increase the levels of this enzyme to compensate for this mutant gene. That could either prevent the development of Parkinson’s or slow down the progression of the disease,” says Vocadlo. “This may even help patients who do not have the mutant gene since lower levels of brain glucocerebrosidase have been observed generally in Parkinson disease patients.”

This project is being jointly supported by the Michael J. Fox Foundation for Parkinson’s Research. Parkinson’s disease is the second most common neurodegenerative disease and there’s currently no treatment that can stop or slow down its progression. Increasing this enzyme activity in the brain is the first goal and the team has made strides towards finding a compound that would achieve this result. They have developed assays and can perform

live-cell imaging to measure the activity of the enzyme after adding different compounds. Eventually, they intend to screen more than 100,000 different compounds

“So far, we’ve screened over 1,000 compounds and even with that small number we’ve identified a couple of compounds now that appear to increase the activity of this enzyme,” Vocadlo says. “The goal will be to identify those that would be most promising to move on into development for a potential therapeutic strategy for Parkinson’s.”

The second part of the project involves developing a method in which they could actually measure the results of a therapeutic in the human brain.“If we’re going to increase the levels of this enzyme, we need ways of being able to monitor how this enzyme is actually operating and how much is present within the brain,” Vocadlo explains.

One way the team intends to accomplish this is by using positron emission tomography (PET) scanning, in which they administer a molecule that will bind to the target enzyme in the brain. This molecule will be radioactive, in a safe dose, and so as it decomposes within the brain it would release positrons, which leads to signals that can be precisely measured.

“We’ve made really good headway there, getting molecules that are now very highly potent, brain-permeable, and clear very rapidly from the brain,” says Vocadlo. “The next steps that we’re undertaking involve tuning of this molecule, and then carrying out initial studies in mice and rats.”

Vocadlo points out that any developments could also apply to Gaucher disease, a lysosomal storage disease in which patients have two GBA mutations, resulting in very low levels of glucocerebrosidase.

Dr. David Vocadlo (Simon Fraser University)“The long-term goal is to identify new compounds that increase the activity of glucocerebrosidase within the brain as a disease-modifying approach to Parkinson’s,” Vocadlo says. “And we hope these technologies would be useful for Gaucher disease as well.”