Validating O-glycosylation inhibitors as a disease modifying therapeutic strategy for Parkinson’s
Simon Fraser University
Currently there are no therapeutics that can slow or stop the progression of Parkinson Disease (PD). Accordingly, there is a major need to identify and advance promising new approaches to tackle this major societal challenge. It has been shown that proteins within the cell are acted upon by an enzyme that modifies certain proteins with specialized sugar residues. Notably, proteins that clump together in the brain and cause the death of neurons, such as alpha-synuclein in PD and tau in Alzheimer Disease (AD), have been shown to be modified with these sugar units. Moreover, the presence of these sugar units prevents these proteins from clumping together. Compounds that block the enzyme that removes this sugar from proteins including alpha-synuclein and tau have shown promise in various models of AD. Accordingly, based on these data, we aim to test whether such an approach could also work in PD models to prevent the formation of toxic oligomers of alpha-synuclein and prevent behavioural defects in a model of PD. Such work could open a new approach to slowing the progression of PD and enable the development of potential therapeutics targeting this pathway.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
We have developed inhibitors of the enzyme that removes this sugar modification from proteins. We therefore have a drug-like molecule that increases brain levels of this sugar modification. Such compounds have demonstrated safety in preclinical models. Accordingly, validating the inhibition of this enzyme in a PD preclinical model would provide a new target to treat PD. Because inhibitors targeting this enzyme are in the clinic, these studies could lead to rapid development of safe and effective therapeutics that slow or halt progression of PD.
We expect our studies in preclinical PD models will define whether or not the strategy of blocking the enzyme that removes this sugar modification is a promising strategy. A positive outcome would support this enzyme being a suitable target to develop a disease modifying approach to PD and should increase attention on this pathway and accelerate the development of compounds targeting this pathway for clinical use in PD.