Mutations in the LRRK2 gene cause familial (inherited) Parkinson's disease (PD). Familial mutations tend to lead to increased kinase (protein regulation) activity or impaired GTPase (type of enzyme) activity of LRRK2 and can also induce toxicity in cultured neurons. The contribution of GTPase activity to the effects of familial LRRK2 mutations has not yet been explored. We have developed a novel pre-clinical model that we will use to evaluate the role of GTPase activity in mutant LRRK2-induced neurodegeneration.
We hypothesize that GTPase activity regulates the neurodegenerative effects induced by the most common G2019S mutation in LRRK2. Our studies will determine how modifying LRRK2 GTPase activity regulates neuropathology.
We will inject viral vectors that express different forms of human LRRK2 in the nigrostriatal (brain system) dopaminergic pathway and will introduce synthetic mutations into the G2019S LRRK2 protein that can alter GTPase activity. The impact of altering GTPase activity on dopamine neuronal degeneration normally induced by the G2019S LRRK2 protein will be evaluated.
Impact on Diagnosis/Treatment of Parkinson's disease:
Our studies will evaluate the contribution of GTPase activity to neurodegeneration induced by the common G2019S mutation in LRRK2 in a pre-clinical model of PD. This study will validate whether GTPase activity represents a new target for therapeutic intervention in PD to prevent the effects of familial LRRK2 mutations. It is anticipated that our findings will be relevant for understanding the mechanisms of neurodegeneration in familial and idiopathic (no known cause) PD and for future drug development efforts.
Next Steps for Development:
Our studies will help to guide the development of future therapies for PD based upon modulating the GTPase activity of LRRK2.