Objective/Rationale:
Inherited mutations that cause Parkinson’s disease have been studied with earnest since their discovery beginning in the 1990’s. These genetic alterations point us to new promising targets for drug discovery. The protein kinase LRRK2 is the most frequently mutated gene in Parkinson’s disease and is therefore a highly studied, novel drug target for PD. Academics and pharmaceutical companies have invested heavily to develop drugs that target LRRK2 in the hopes that these may prevent the onset or slow the progression of PD. It has yet to be established if directly targeting LRRK2 will have any detrimental outcomes. Our goal is to provide pre-clinical understanding of how to target LRRK2 and the molecular events that occur after LRRK2 drugs are administered.
Project Description:
LRRK2 contains a central catalytic domain, as well as flanking regions which can regulate the kinase activity of the enzyme. The kinase catalytic domain is the main target for drug development. Using biochemical and genetic tools, we will characterize specific molecular consequences of inhibiting LRRK2 with small molecules, examining post-translational modifications of the protein in short versus long-term inhibition. We will also study the extra-catalytic (flanking) regions of LRRK2 to explore the viability of these domains as other drug targets. These flanking regions also receive signals from the cell or regulate LRRK2 themselves. We will examine signaling inputs to these regions to assess their impacts on the overall biology of LRRK2 as it relates to LRRK2 drug administration.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Since LRRK2 drugs are a new hope for PD, our studies of the extra-catalytic regions will provide insights on if these domains are new aspects of LRRK2 are attractive as new drug targets. Furthermore, our results from understanding the molecular events that are subsequent to LRRK2 drug treatment will enable development of safe and efficacious new treatments for PD that target LRRK2.
Anticipated Outcome:
We will better understand the LRRK2 holo-enzyme as a drug target by characterizing the regulation of the extra-catalytic regions and analyzing how these regions influence catalytic activity of the enzyme. By investigating the consequences of LRRK2 inhibition, we will understand if drugs targeting LRRK2 kinase activity yield undesirable outcomes.