Promising Outcomes of Original Grant:
Mutations (changes) in the LRRK2 gene are a leading genetic cause of Parkinson's disease (PD). Previously, we sought to evaluate the connection between a common PD-linked LRRK2 mutation and neurodegeneration. Specifically, we wanted to test whether GTPase activity of the LRRK2 protein -- its ability to speed certain chemical reactions within the cell -- is involved in neurodegeneration. Using genetic methods, we turned off the GTPase activity of LRRK2 in pre-clinical models carrying the mutation linked to Parkinson's. This reduced neurodegeneration, supporting a role of GTPase activity in the disease-causing effects of the LRRK2 mutation.
Objectives for Supplemental Investigation:
To extend these promising findings, we will study the ability of other LRRK2 mutations to cause Parkinson's in this pre-clinical model. We will study how these mutations influence neurodegeneration by changing the activity of LRRK2. We will also evaluate whether deactivating LRRK2 in this model can stop or slow neurodegeneration.
Importance of This Research for the Development of a New PD Therapy:
In the course of this study, we will develop new and useful pre-clinical models with features of inherited PD based upon LRRK2 mutations. We will also determine how LRRK2 activity contributes to neurodegeneration. These studies will guide drug discovery efforts for developing novel drugs that deactivate LRRK2 to treat PD. They will also provide support for the use of drugs called LRRK2 kinase inhibitors to prevent neurodegeneration.