Mutations in the Parkin gene are responsible for a familial form of Parkinson’s disease (PD). The gene encodes a protein whose activity has been shown to protect neurons from death. Researchers hypothesize that increasing the activity of Parkin could be a therapeutic strategy in PD. This project will use a recently determined 3D-structure of Parkin to design an assay (characterization test) to screen for drugs that will enhance its activity.
Based on the structure of the Parkin protein, scientists have identified the Repressor Element of Parkin (REP) that binds and blocks a site named RING1 that is required for its activity. An ultimate goal is to find a drug that will disrupt the REP:RING1 interaction through conformational changes, in order to activate Parkin. Researchers propose two approaches to detect disruption of the REP, which they can use to screen for drugs. The first approach consists of monitoring binding of a fluorescent REP peptide that will bind to RING1 in vitro. The second approach will make use of a technique called FRET to monitor conformation changes, which will reflect Parkin activation in cells. The two approaches are highly complementary and will feed off one another.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Upon successful development of the assays described above, the project will naturally feed into high-throughput screening of drugs that activate Parkin. These drugs have the potential of becoming PD therapeutic agents that will prevent or slow down the progression of the disease. As such, this is the first rational chemical biology approach to increasing the activity of a recessive PD gene serving a neuroprotective function in vivo.
By the end of this one-year project, researchers will have developed a set of tools that can be used not only to screen for drugs, but also to investigate the function of Parkin. In particular, the FRET assay will allow scientists to study the conformational changes and activity of Parkin in cells. Moreover, the assay will allow the identification and characterization of endogenous (“natural”) activators of Parkin in cells.