Role of LRRK2 in the Regulation of Dopamine Receptor Trafficking

Study Rationale:
Mutation of the LRRK2 gene is the greatest known genetic contributor to Parkinson’s disease. However, the molecular mechanisms and pathological pathways by which LRRK2 induces neuronal death remain elusive. Evidence indicates a potential role of LRRK2 in the regulation of neuronal vesicle trafficking. In this prospect, the main objective of our project is to analyze the role of LRRK2 in the regulation of dopamine receptor trafficking.

Hypothesis:
We will analyze the role of LRRK2 in the regulation of dopamine receptor trafficking in cellular and pre-clinical models expressing wild type (normal) or LRRK2 pathological mutations.

Study Design:
The study will be performed with cellular and pre-clinical models that express dopamine receptors in the absence or presence of LRRK2. We will induce dopamine receptor internalization and recycling or degradation. The dopamine receptors trafficking will be evaluated using three different experimental approaches.

Impact on Diagnosis/Treatment of Parkinson’s Disease:             
Understanding more about the role of LRRK2 in disease can illuminate new targets or approaches for therapies to slow or stop Parkinson’s progression.

Next Steps for Development:
The identification of molecular pathways that mediate LRRK2 neuronal toxicity remains a critical goal to develop more effective therapeutic strategies or to define new potential markers to follow the disease onset and progression.