Funded Studies
This grant builds upon the research from a prior grant: The Role of LRRK2 in Neurotransmission
Objective/Rationale:
Many of the motor symptoms in Parkinson’s disease (PD) are attributed to a deficit of the neurotransmitter dopamine in the brain region called the striatum. Recent studies show that mutations in the gene LRRK2 underlie familial PD, and that the protein LRRK2 modulates dopamine in the striatum. We plan to determine how LRRK2 affects dopamine release and whether it controls the function of striatal neurons. First, we have to understand the normal brain function of these proteins in order to understand how they are rendered dysfunctional by gene mutations.
Project Description:
The brain region most affected by cell death in PD (the substantia nigra) releases dopamine into another brain region called the striatum. These two regions interact to help the brain evaluate and plan physical (motor) and mental (cognitive) actions. Here, we will study the interplay between this dopamine release and the other important glutamate inputs to the striatum. We will use normal pre-clinical models and ones with either too little or too much LRRK2, which enables us to work out the effects of these different biological situations.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Mutations in the LRRK2 gene are the most common cause of familial (hereditary) Parkinson’s disease. Studying effects of the gene product, the LRRK2 protein, on dopamine release and striatal neuronal function will help us to better understand mechanisms of brain dysfunction in all cases of PD and provide new targets for drug therapy.
Anticipated Outcome:
We expect to uncover how LRRK2 regulates cell communication in the striatum. Results will help us develop new ways to normalize the function of these neurons, with potential for delaying onset of symptoms and/or slowing progression of Parkinson’s disease.