Parkinson’s disease is the most commonly diagnosed neurodegenerative disorder after Alzheimer’s and may affect one in 500 people in their lifetime. Symptoms include tremors, muscle stiffness, and impaired balance and coordination that worsen over time.
The exact cause of Parkinson’s is unknown, but Simon Fraser University (SFU) Professor David Vocadlo’s Laboratory of Chemical Biology is developing new methods to understand how this and other diseases develop and progress.
Vocadlo holds a joint appointment in the Departments of Chemistry and Molecular Biology and Biochemistry. He is Co-Director of the Centre for High-Throughput Chemical Biology, an award-winning scholar and inaugural Fellow of the Royal Society College of New Scholars and Scientists. His research group investigates glycoconjugates, carbohydrates that bind with other molecules and contribute to health and disease.
Research supervised by Vocadlo and led by former PhD student and now Postdoctoral Fellow Matthew Deen and Senior Research Associate Yanping Zhu developed new chemical biology tools to examine the activity of glucocerebrosidase (GCase), an enzyme commonly linked to Parkinson’s. The study showed that the activity of lysosomal GCase in patients is similar in both blood cells and brain cells—an important finding because it could allow a simple blood test to monitor how Parkinson's progresses in the brain.
The study, A versatile fluorescence-quenched substrate for quantitative measurement of glucocerebrosidase activity within live cells was recently published in the Proceedings of the National Academy of Sciences of the USA.
The methods and tools developed in Vocadlo’s lab may also help researchers develop a better understanding of other neurodegenerative diseases linked to GCase such as Dementia with Lewy Bodies and Gaucher's Disease, a rare disease that usually manifests in childhood.
We talked with Professor Vocadlo about his research.
Can you tell us more about the new chemical biology tools you are developing your lab?
In general, we focus on creating chemical tools that include antagonists of various proteins in mammalian systems as well as new substrates of enzymes that allow one to see these enzymes working in cells and tissues. New antagonists of less studied enzymes are important research tools that help biologists explore their roles in biology and potential therapeutic potential in living systems.
We work using the Centre for High-Throughput Chemical Biology (HTCB) at SFU for this purpose. For enzyme substrates we work on creating molecules that can be used with modern microscopes to see enzymes working and measure how active they are within cells. More specifically, for the enzyme GCase we realized there was a real gap in the field and new tools were needed by the community—both academia and industry.
These substrates are the result of a lot of effort and coming back from various dead ends. The fluorescence quenched design of these substrates make them dark until GCase in lysosomes processes them, relieving the quenching and making the product very bright. The substrates incorporate a number of carefully designed chemical features that enable them to work efficiently and allow one to tune their colours as desired. More broadly, we are focused on working to create substrates for other enzymes linked to various other diseases and using these substrates to uncover fundamental biology.
How might this work lead to new diagnostics and treatment of Parkinson’s and other diseases?
Mutations in the GBA gene that encodes GCase have emerged as the greatest genetic risk factor for Parkinson’s disease (PD). Patients that have mutations have an earlier age of onset of disease and more rapid progression. Irrespective of mutations in GBA, Parkinson patients seem to have lower enzyme activity. Moreover, increasing the activity of this enzyme in preclinical models also protects against disease. So many speculate the dysfunction of this enzyme may be central to disease progression. For these reasons, being able to monitor the activity of the enzyme in patient blood samples could be a useful clinical tool, used in combination with other clinical assessments, to help diagnose PD early on. Such an approach could also be used in theory, to monitor the progression of disease.
How does chemistry and biology intersect in your work, and how important is this interdisciplinary collaboration?
Chemistry and biology have significant intersections. This is seen most commonly in the development of new therapeutics for diseases, where chemistry plays a central role in creating new chemical matter that can interact with biology in a useful way. Over the past couple of decades, the use of chemical principles and chemical tools to study biology systems has emerged as a distinct discipline called Chemical Biology. This is the central effort of our team—we seek to identify needs in the biological community and to create new chemical tools and strategies that can be used to address those gaps. To do this the team is composed of both chemists and biologists, who bring complementary ways of thinking about problems and enable new tools to be validated as being useful. We also collaborate widely with experts in specific diseases including clinicians as well as focused disciplines including, for example, structural biology or other branches of chemistry—both in industry and academia. These collaborations enable wider impact of the work.
What is happening next in your research on glycoconjugates (carbohydrates)?
We are fascinated by the emerging importance of small compartments within cells called lysosomes. These were traditionally considered the recycling bin of the cell where unneeded proteins and other structures went to be reused. However, they have emerged as having many diverse roles in regulating cell function. One particular area of interest is their function within the brain where they act in an important way to remove potentially harmful materials. We are working to understand how the activity of these enzymes in the lysosomes that degrade glycoconjugates are regulated. An improved understanding of these areas could help explain why their function is important in various neurodegenerative diseases. As part of our work, we have developed several rewarding collaborations with both academic and industrial groups—all of whom are doing really exciting and progressive work in different areas.
This work was sponsored by the Michael J. Fox Foundation for Parkinson’s Research and the Canadian Glycomics Network. The multinational Roche also collaborated on aspects of this work.