Consequences of LRRK2 Rab Phosphorylation in Neurons and Astrocytes

Study Rationale:
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are important contributors to LRRK2-linked Parkinson's disease (PD); therefore, LRRK2 is an important drug target. The goal of this project is to understand how LRRK2 modifies the functions of proteins called Rab GTPases, which were recently identified as major targets of. In addition, these proteins have also been linked to cell death in PD. Findings from this study will help us understand how LRRK2 mutations cause disease and, potentially, how drugs that block LRRK2 affect cell function. We will study neurons and astrocytes (cells that support neurons), since both cell types support normal brain function, and LRRK2 is especially abundant in astrocytes.

Hypothesis:
Our hypothesis is that LRRK2 inactivates certain Rab proteins; our goal is to test the function of neurons and astrocytes in the absence of Rab proteins.

Study Design:
Dr. LaVoie, Dr. Pfeffer and colleagues will obtain cultured neurons and astrocytes that lack a particular Rab protein to study the normal function of these cells.

Impact on Diagnosis/Treatment of Parkinson's disease:
Results from this study will help us better understand how LRRK2 mutations cause disease, and, potentially, how drugs that block LRRK2 affect cell function. This research may also help anticipate drug side effects and improve drug design.

Next Steps for Development:
As LRRK2 inhibitor drugs get closer to clinical application, it is essential that we understand precisely how they work to provide the best guidance for their use.