Objective/Rationale:
Inherited mutations in a gene called LRRK2 have recently been discovered to cause Parkinson’s disease. The LRRK2 gene encodes an enzyme called a kinase, which is more active when found mutated in Parkinson’s disease patients. Studies indicate that this extra activity is harmful, making LRRK2 a candidate for drug therapies that could stop the enzyme activity in patients. We aim to elucidate the role of LRRK2 in order to develop a means to test possible LRRK2 based treatments.
Project Description:
We have developed a system of studying the LRRK2 enzyme in the lab and will use state of the art techniques in the field of mass spectrometry to discover the unknown role of LRRK2. When this role is uncovered, we will develop a method to measure the direct effect of the LRRK2 activity.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The results of our work will provide insight into the role of LRRK2 in the brain. This knowledge and the methodologies we develop will facilitate the development of new drugs that target the LRRK2 enzyme. Interestingly, the class of drugs that inhibit enzymes like LRRK2 have been used for many years in the treatment of diseases like chronic myelogenous leukemia and we hope for similar end results with LRRK2.
Anticipated Outcome:
At the end of this project, we hope to have identified novel targets for LRRK2, which could reveal unrealized roles for this enzyme in the brain. We will expect these discoveries to help in the development of drug therapies to treat Parkinson’s disease by targeting LRRK2. This will be a valuable resource to the Parkinson’s disease research community as well as pharmaceutical discoveries for the treatment of disease.
Final Outcome
We are working to identify interacting proteins of LRRK2 and potential molecules on which the LRRK2 enzyme acts (called ‘substrates’), with the immediate goal of developing an in vivo assay for the kinase activity of LRRK2. This will allow for the downstream, in vivo validation of small molecule inhibitors of the enzyme. Utilizing state of the art mass spectrometry methodologies, we have defined some protein:protein interactions with LRRK2 and are beginning to understand the upstream inputs and downstream substrates for the LRRK2 kinase activity. When we have validated substrates, we will develop antibody reagents to detect LRRK2 specific modifications of those substrates in vivo.