Study Rationale:
Mutations in the gene GBA1, are the most common genetic risk factor for Parkinson Disease (PD). Mutations in GBA1 lead to malfunctioning of the protein glucocerebrosidase, which acts to breakdown unneeded components of the cell. Oddly, only 10% of those people who have mutations in GBA1 develop PD. This indicates that there are likely other genes that affect glucocerebrosidase activity. Knowledge of these genes that affect glucocerebrosidase activity could help develop drugs that increase the activity of this important enzyme. Increasing its activity may block the toxic clumping together of the protein alpha-synuclein, which plays a central role in PD.
Hypothesis:
There are unknown genes that influence the activity of glucocerebrosidase and identifying these could open the door to the creation of new therapeutics that increase the activity of glucocerebrosidase within the correct parts of the cells to prevent progression of disease.
Study Design:
We devised chemical tools to measure the activity of glucocerebrosidase in living cells. We have also started to examine the effects on glucocerebrosidase of deleting each gene in the human genome in cancer cells. Here we merge these approaches and apply them to human patient neurons having PD-relevant mutations in GBA1. Using this approach with physiologically relevant cells, we will analyze the effects of increasing or decreasing the expression of all genes in the human genome on cellular glucocerebrosidase activity within these disease relevant human neurons. Initial follow up will identify the most promising genes that can improve glucocerebrosidase activity.
Impact on Diagnosis/Treatment of Parkinson’s disease:
The identification of genes that can desirably affect glucocerebrosidase activity will open up new therapeutic targets that can be pursued to create new drugs to combat Parkinson disease. The results of our work will be helpful to the entire community investigating glucocerebrosidase as a potential treatment strategy.
Next Steps for Development:
Using our new chemical tools in combination with physiologically relevant cell models to identify genes that influence glucocerebrosidase will allow the wider community to examine these genes and pursue the most promising ones to create new medicines for Parkinson disease.