In Vivo Rescue of Dopamine Release Deficits via Kinase Inhibition in LRRK2 Mutant Mice

Objective/Rationale:             
Abnormal kinase activity is thought to be responsible for the pathogenic effects of LRRK2 in parkinsonian patients and many lines of evidence point towards a role of LRRK dopamine neurotransmission. We have created pre-clinical models of a LRRK2 mutation that display abnormalities in dopamine release and metabolism, which we hypothesize may be similar to the early brain changes in Parkinson’s patients. This study will utilize our novel model and a newly developed LRRK2-specific kinase inhibitor, to establish the relationship between LRRK2 kinase and dopamine neurotransmission using a real-time readout.

Project Description:             
We will use an experimental technique called microdialysis, which allows us to collect small amounts of fluid from the brain. The amount of dopamine and dopamine breakdown products (metabolites) are measured from this tiny sample using a chromatographic technique. We will compare the amount of dopamine and metabolites in samples from normal and mutant LRRK2 models, before and after LRRK2 inhibitor drug treatment. If the levels of dopamine in the drug-treated models rise towards the levels of dopamine in normal untreated mice, this will tell us that LRRK2 kinase is directly involved in dopamine release.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Kinase enzymes are considered highly druggable targets and LRRK2 kinase inhibitors are already being developed by drug companies.  By establishing a functional link between LRRK2 kinase activity and dopamine transmission, this work will provide additional rationale for the development of LRRK2 kinase inhibitors as Parkinson’s therapeutics.

Anticipated Outcome:          
In addition to providing therapeutic rationale, establishing this functional link between LRRK2 kinase activity and dopamine will guide future studies aimed at defining specific molecular pathways involved in dopamine neuron demise. In turn this will facilitate the nomination of more drug targets within a signaling pathway and the identification of biomarkers to aid earlier detection of disease.