Promising Outcomes of Original Grant:
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) account for up to 13% of familial Parkinson's disease (PD) patients, but the function of LRRK2 is poorly understood. Previous data from this group shows that LRRK2 regulates synapse development in cultured neurons. Synapses are the structures that allow neurons to send signals to other cells. Glutamatergic terminals (synapse receptors) are larger and undergo more rapid release in neurons lacking LRRK2. Conversely, neurons expressing the LRRK2 G2019S mutation have smaller excitatory terminals and an increased density of inhibitory synapses. These data suggest that LRRK2 normally constrains vesicle number and release kinetics at excitatory terminals, while its activity enhances development of inhibitory synapses.
Objectives for Supplemental Investigation:
Researchers hypothesize that LRRK2 regulates the formation of synapses between neurons, the generation of neural networks, and the balance of excitation (more likely to cause an action after sending a signal) and inhibition (less likely to cause an action). This project will first determine how LRRK2 regulates excitatory and inhibitory synapse formation in a part of the brain called the hippocampus. Then it will test the prediction that changes observed there will be shared by neurons in another part of the brain, called the dorsal striatum, a functional target of Parkinson’s disease.
Investigators will use anatomical and genetic approaches to identify and characterize deficits in anatomical pathways vulnerable to changes in LRRK2 expression or activity. And finally, they will develop a circuit-specific experiment for analysis of LRRK2 function that can be used to screen pharmacological inhibitors.
Importance of This Research for the Development of a New PD Therapy
The identification of biological actions driven by LRRK2 activity will permit a finer focus on circuits vulnerable to LRRK2 mutation and the development of PD. These findings will provide a more robust system for identifying targets of LRRK2 and screening the actions of potential therapeutic agents targeting LRRK2.