Objective/Rationale:
A promising target for neuroprotective therapies in Parkinson’s disease has emerged in the LRRK2 protein kinase. Proteins with similarities to LRRK2 have been successfully targeted in other diseases, most notably cancer, with tremendous clinical success. To identify the most efficacious therapies that specifically target LRRK2 activity, technology must be developed to visualize this activity. Our objective is to develop the methods to assess LRRK2 activity directly from tissue in pre-clinical models relevant to Parkinson’s disease.
Project Description:
We will use a relatively selective pharmacological agent, which can inhibit LRRK2 activity, at a variety of doses in a pre-clinical model to derive a panel of tissue that includes brain and cerebral spinal fluid to assess the phosphorylation status and activity-dependent conformation of LRRK2. This proof-of-principle project will help pave the way for the evaluation of more potent and specific compounds that target LRRK2 activity in pre-clinical models required for pre-clinical testing.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This project will further characterize LRRK2 as a neuroprotective target and, if successful, identify methodology to hasten the identification and development of the best therapies for use in human clinical trials and in patients with Parkinson’s disease.
Anticipated Outcome:
We expect to see significantly reduced formation of active LRRK2 conformations in tissue derived from pre-clinical models treated with compounds that inhibit LRRK2, in a dosage dependent manner. Similarly, we expect to see reduced levels of phosphorylated protein. Ultimately, this project will determine the suitability or identify major caveats to the usage of LRRK2 conformation and phosphorylation as activity dependent markers in the search for neuroprotective agents in Parkinson’s disease.