Objective/Rationale:
Excessive activity of a human enzyme, named “LRRK2”, is closely associated with Parkinson’s Disease (PD). Small chemical compounds that inhibit this enzyme may be extremely helpful in understanding the mechanics of the disease. More importantly, these compounds may lead to drugs that provide effective treatments for PD. The goal of this proposal is to develop a sensitive, high-throughput and inexpensive method to screen thousands of compounds to detect those that are able to inhibit the LRRK2 enzyme.
Project Description:
The LRRK2 enzyme is not active as an individual molecule; instead, it must bind to another copy of itself to form an active “dimer.” We plan to develop a novel fluorescent assay to detect compounds that prevent formation of the dimer. Screening of LRRK2 compounds will be accomplished using a straight-forward label-free, reagent free biosensor platform exploiting the fluorescent property of a novel YFP molecule. Chemical compounds that interfere with formation of LRRK2 dimers will prevent fluorescence from YFP. Selectivity and specificity of the identified compounds will be validated subsequently through further assays. We will work with major pharmaceutical companies to screen thousands of compounds that are available.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If successful, our project will allow researchers to screen thousands of compounds for the ability to prevent activation of LRRK2. Because LRRK2 plays a key role in PD, we expect that many of the new compounds will have potential as drugs to treat PD patients. In addition, the chemicals will be useful research tools to discover other human proteins that interact with LRRK2. This knowledge will further enhance our ability to understand and hopefully to treat or prevent PD.
Anticipated Outcome:
Successful outcome of the proposed plan would result in development of a full-length LRRK2 cell based assay for a novel screening platform. We expect this work to provide valuable information on what classes of molecules are most effective in inhibiting LRRK2. This knowledge will be useful for discovery and synthesis of drugs to treat PD.