Objective/Rationale:
Loss of parkin protein in humans leads to loss of dopamine neurons and ultimately Parkinson’s disease (PD). Loss of parkin activity is linked to young-onset familial PD, as well as sporadic, later-onset PD. Restoration of parkin protein, or activity, is neuroprotective. Parkin has recently been discovered to exist in an “on” and “off” state. The goal of this research project is to identify small molecules that will activate parkin to the on state, resulting in prevention of further neuronal loss in PD.
Project Description:
We have designed a novel method of screening for parkin that will directly identify small molecules that turn parkin from off to on. Purified parkin protein, along with proprietary screening tools, will be introduced to 75,000 unique small molecule compounds. Any compounds that result in parkin on will be categorized as hits and selected for further analysis. Identification of these specific hit molecules will be the starting point to develop therapeutic compounds for testing in pre-clinical models of PD, and ultimately, humans.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Development of a specific parkin-activating compound has the potential to prevent further neuronal loss in sporadic PD patients, as evidenced by its demonstrated neuroprotective role in pre-clinical models. As yet, no therapy has been directed towards parkin protein in PD, representing a significant gap in the potential avenues for intervention. While PD is a complex disorder, any agent that can halt the neuronal loss definitive of the disease is an important avenue to pursue.
Anticipated Outcome:
This project will provide for identification of lead compounds for drug development, as well as tool compounds for research purposes. Studies with these compounds may not only lead to new therapies for PD, but may ultimately identify additional avenues of intervention in the neurodegeneration characteristic of PD.
Final Outcome
A loss of protein parkin or its activity, i.e., ability to perform its function, has been linked to Parkinson’s disease (PD). The goal of this project was to identify small-molecule compounds that will protect neural cells from damage in PD by activating parkin. In this project, we identified several new small-molecule compounds that activate parkin. These compounds can increase the ability of parkin to protect cells from damage. Several of these compounds have been studied extensively, and we now understand how they activate parkin. We have identified two key parts of the parkin protein to which the compounds attach to activate it. The compounds and technology we developed in this project will serve as a starting point in the search for promising therapeutic candidates suitable for further evaluation in pre-clinical models and, ultimately, clinical trials.
Presentations & Publications
We are currently working on a publication for one of our tool compounds—when this work has been refined for public consumption I am happy to submit the version that will be published.