Study Rationale:
One of the most common inherited causes of Parkinson's disease (PD) is defect in the LRRK2 protein caused by changes, or mutations, of the LRRK2 gene. LRRK2 regulates the movement of cellular parts around and into/out of the cell in a process known as trafficking. It does this by deactivating another set of proteins called Rabs. In this study, we will use modified cells to learn how mutations of the LRRK2 gene alter or affect this trafficking process. These insights, in turn, could be used to develop therapies to correct the cellular defect caused by mutation of LRRK2.
Hypothesis:
The tools and data developed in this work will allow us to understand how mutation of LRRK2 affects other proteins in the cell, for example, the Rab proteins, and how that subsequently alters protein trafficking.
Study Design:
We will develop cells with molecular tracers, proteins whose movement within the cell can be tracked with high precision in a high-resolution microscope. Using these precise sensors of protein movement, we will look at differences between normal and mutant LRRK2. We also will examine how mutation of LRRK2 affects its ability to deactivate Rabs and traffic proteins within the cell.
Impact on Diagnosis/Treatment of Parkinson's disease:
With a better understanding of how and why LRRK2 mutation alters the movement of proteins within cells, we can better design the search for therapies to correct the dysfunction caused by LRRK2 mutation. Such treatments might help stop the progression of LRRK2-associated Parkinson's and could potentially be used to prevent disease onset in people who have LRRK2 mutations.
Next Steps for Development:
Once we have identified the molecules that are damaged by LRRK2 mutation, we can develop methods to screen for therapies that restore those molecules. The experimental methods to study trafficking developed in this work could be used to screen for other potential therapeutic approaches in PD.