Mutations in the lysosomal (enzyme storage unit) enzyme GCase are associated with an increased risk of Parkinson's disease (PD) and cause alpha-synuclein (protein associated with Parkinson's) clumping in many model systems. LRRK2 is another protein associated with genetic forms of PD that is linked to lysosome biology. Functional interactions between these two disease-related proteins will be examined.
We hypothesize that mutations in GCase alter LRRK2 signaling and contribute to GCase-dependent changes in alpha-synuclein metabolism.
Using cellular models, we will investigate whether changes in GCase activity or its expression lead to changes in lysosome function and morphology. In addition, we will examine these cells for changes in LRRK2 signaling and determine whether LRRK2 kinase inhibitors reverse some of the changes in GCase models.
Impact on Diagnosis/Treatment of Parkinson's disease:
LRRK2 kinase inhibitors are currently in development for the treatment of individuals who carry LRRK2 mutations and may be suitable for others with PD. Here, we will determine if those who carry genetic alterations in GCase should be considered for such treatments, once established.
Next Steps for Development:
These pilot experiments, if successful, will support further research and validation, as there are several pre-clinical models of GCase mutations.