Objective/Rationale:
Exactly how Parkinson’s disease (PD) develops is not known, however current research indicates that the leucine rich repeat kinase 2 (LRRK2) protein plays a central role in the disease. LRRK2 is a cellular signaling protein, in other words it’s a protein involved in fine tuning how cells run by turning cellular processes on and off. Finding out what flips LRRK2’s on-off switches may be crucial to understanding PD pathogenesis and to developing novel PD therapies.
Project Description:
Here we will study the regulation of one such on-off switch involving adding and removing phosphates from LRRK2. LRRK2 cellular phosphosites are dynamically regulated. For instance, several LRRK2 disease mutants display reduced cellular phosphorylation compared to wild type LRRK2. Also, cellular treatment with compounds inhibiting LRRK2 kinase activity leads to dephosphorylation of LRRK2. In our international collaboration between the K.U.Leuven (Leuven, Belgium) and the Parkinson’s Institute (Sunnyvale, CA, USA), we have developed several reagents and methods to robustly measure LRRK2 cellular phosphorylation. We will use these tools combined with unbiased reverse genetics screens, to identify phosphatases involved in the dephosphorylation of LRRK2 cellular phosphosites. Hits from the screening will be extensively tested in vitro and in cells in order to confidently nominate the LRRK2 phosphatase.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Identifying the LRRK2 phosphatase is relevant to both potential PD treatments and PD diagnosis. Indeed, small molecule inhibitors of LRRK2 kinase are in development as potential PD drug therapies, and it is crucial to understand the LRRK2 kinase inhibitor induced dephosphorylation of LRRK2. Also, since the LRRK2 phosphatase dynamically regulates LRRK2 in cells, it is likely to point to new possibilities of targeting LRRK2 activity or of developing LRRK2 based biomarkers of disease progression.
Anticipated Outcome:
Our project is expected to reveal a protein that flips one of LRRK2’s on-off switches, namely the phosphatase involved in regulating the LRRK2 cellular phosphorylation sites. We will also begin to characterize how the LRRK2 phosphatase impacts LRRK2 function. The knowledge and tools generated in the project will be useful in investigating the link between LRRK2 (de)phosphorylation and PD pathology in follow up studies.