Objective/Rationale:
Parkinson disease involves loss of the neurochemical dopamine, and many of the motor symptoms are attributed to a dopamine deficit in the brain region called the striatum. Recent studies show that mutations in the gene LRRK2 underlie familial Parkinson disease, and we have found that the protein LRRK2 modulates levels of dopamine in the striatum. We plan to determine how LRRK2 affects dopamine release and the function of striatal neurons.
Project Description:
To better understand the mechanisms underlying effects of LRRK2 on dopamine release and striatal neuronal function, we will compare these processes in two pre-clinical models with either high levels or low levels of LRRK2. In brain tissue from these pre-clinical models, we will measure the electrical signals generated by striatal neurons, which are modulated by dopamine. We can then use different drugs to inhibit or activate receptors for dopamine on these neurons to determine if dopamine regulation differs among the three pre-clinical models, which would be one indicator that release of dopamine is abnormal in the brain tissue of the model with too much or too little LRRK2. To further investigate the reasons why dopamine release is altered, we will also measure electrical signals from the dopamine-releasing neurons themselves.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Mutations in the LRRK2 gene are the most common cause of familial (hereditary) Parkinson disease. Studying effects of the gene product, LRRK2, on dopamine release and striatal neuronal function will help us to better understand mechanisms of brain dysfunction in sporadic Parkinson disease, and provide new drug targets for therapy.
Anticipated Outcome:
We expect to uncover mechanisms underlying the dopamine deficit in Parkinson disease, and determine the earliest effects of this deficit on striatal neuronal function. These findings will help to develop new ways to normalize the function of these neurons, with potential for delaying onset of symptoms and/or slowing progression of disease.