Enzymes are biological machines which facilitate crucial processes in the human body. A reduction in the function of a given enzyme, sometimes brought about by an alteration or “mutation” to the underlying genetic code, often results in disease. In Parkinson’s disease (PD), a mutation in the GBA1 gene can cause earlier disease onset and rapid motor decline. Furthermore, the enzyme glucocerebrosidase (GCase) that is encoded by GBA1 is less active in PD patients regardless of whether they have a defective GBA1 gene.
The researchers hypothesize that GCase is altered or “modulated” by other proteins within the cell. The first goal in this project will be to create improved ways to measure the activity of GCase in live human cells. Previous work has shown that “ratiometric fluorescence sensors” – small molecules which light up when processed by a target enzyme – have high efficacy towards this end. The activity of a large library of existing drug candidates will then be tested for their ability to modulate GCase. Changes measured in GCase activity within cells treated with these drug candidates will help identify these aforementioned unknown “modulators”, thus revealing new insights into the mechanisms of PD and opening new therapeutic approaches.
Dr. Nicholas See obtained his PhD with the Dean’s Award in 2023 from the University of Queensland, Australia. Guided by Prof. Vito Ferro, his PhD research entailed the chemical synthesis and computational modelling of rare L-hexoses. He then completed a brief appointment at the Ferrier Research Institute, New Zealand, where he worked with Prof. Richard Furneaux on the photochemistry of carbohydrates. In 2024, Dr. See moved to Simon Fraser University, Canada to commence a postdoctoral research fellowship under Prof. David Vocadlo.
Dr. See has an ongoing research interest in exploiting physical organic chemistry to address complex challenges in carbohydrate synthesis. This strategy underpins his current research project which is focused on the development of new chemical tools for studying neurodegenerative disorders.