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Functional Analysis of LRRK2

LRRK2 is a gene that, when not working properly, causes Parkinson’s disease. However, the function of this large gene and its involvement in the disease process is virtually unknown. In order to find a better treatment of Parkinson’s disease, we need to know what is the precise role of LRRK2 in cell function and how exactly its dysfunction contributes to cell death. Therefore, we are focusing our research efforts on defining the interacting partners and elucidating molecular pathways of LRRK2.

Project Description
We will use three complementary approaches that will help us better understand the LRRK2 biology. First, we have generated and characterized a LRRK2 fruitfly.  We will use the power of fruitfly genetics to perform a large screen in search for interacting partners of LRRK2. Second, we will characterize LRRK2 knockout mice (mice that don’t have LRRK2 protein). We will perform a wide range of experiments, primarily looking at possible changes in motor behavior and in the functioning of the dopamine system. We will also further characterize our LRRK2 knock-in mice (mice that have a Parkinson’s disease –associated LRRK2 mutation), especially in respect to their susceptibility to a parkinsonism-causing neurotoxin MPTP. Third, we will use our LRRK2 mice and venous blood samples from Parkinson’s disease patients to dissect the molecular pathways of LRRK2 and its interacting partners discovered in our genetic screen in a human context.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
We are hoping that knowing the interacting partners of LRRK2 and understanding the molecular pathways will give us new targets that can ultimately be used for development of better treatments of Parkinson’s disease.

Anticipated Outcome
Once we are finished with our project, we expect to have a much clearer understanding of the role that LRRK2 plays in Parkinson’s disease, including what other proteins it interacts with and what cellular processes it affects. This may open new avenues of research that will ultimately answer the question why are dopamine cells dying in this disorder and what can we do to stop this progressive deleterious process.


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