The LRRK2 enzyme regulates proteins through a process called phosphorylation. The LRRK2 gene, which is mutated in familial Parkinson's disease (PD), an inherited form of PD, can regulate a class of proteins called Rab GTPases (Steger et al., 2016). These proteins play a role in the transportation of vesicles (storage packets) in the cell. Mutated versions of LRRK2 inactivate certain Rab proteins, a process that likely contributes to PD. LRRK2 can be blocked by small molecules that may delay or prevent PD, and Rab proteins could serve as markers of disease activity, or biomarkers. The aim of this project is to determine whether Rab proteins can be used as clinical markers for the effectiveness of small molecule inhibitors of LRRK2.
We hypothesize that it is possible to develop assays (analytic tests) to reliably and sensitively detect Rab proteins in human cells and body fluids. Our goal is to combine the expertise of five laboratories that have a major interest in LRRK2 and Rab biology to develop state-of-the-art chemicals and technology to evaluate LRRK2-phosphorylated Rab proteins and related proteins.
We will use body fluids from individuals with PD (plasma, cerebrospinal fluid (liquid that baths the brain and spinal cord) and blood cells) to determine whether and which Rab proteins could be used as clinical markers for determining LRRK2 drug efficacy. We will use multiple methods to study these potential markers, including protein mass spectrometry (measures the number of chemicals in a sample) and biochemistry assays. Using these powerful methods, the identity and quantity of proteins can be determined with high precision.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Since LRRK2 directly affects Rab proteins, we aim to see if these proteins are found in human body fluids and, if so, whether they can be used to measure the effectiveness of LRRK2-based therapies.
Next Steps for Development:
If successful, the methods developed to detect these proteins could be incorporated into clinical trials to determine the optimal dose of LRRK2 inhibitors and their efficacy in affecting these proteins