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Pharmacological Modulation of Parkin Expression and Function to Attenuate Mitochondrial Dysfunction

This project aims to identify drug-like molecules that increase the amount of the protein parkin in neuronal cells. Parkin is mutated in some people with Parkinson’s disease (PD). Parkin removes damaged mitochondria (the powerhouses of the cells), which protects neurons from cell death. After developing new molecules that increase levels of parkin, our goal is to determine their therapeutic potential in PD models and to characterize how the drugs increase parkin levels.

Project Description:
Using state-of-the-art drug discovery technology, we will screen hundreds of thousands of molecules from libraries of clinically approved drugs, pharmacologically active compounds isolated from natural sources, and diverse drug-like agents produced by chemists. This large-scale screening will be done with cells engineered to report changes in parkin protein levels induced by the application of a potential drug. After the screens have identified candidate molecules that may be relevant to PD treatment, we will use medicinal chemistry techniques to increase their effectiveness and decrease their potential undesirable side effects. We will then test the most optimal molecules in pre-clinical models to demonstrate their benefit. This effort will be achieved through the teamwork of biologists and chemists from multiple scientific teams within the National Institutes of Health.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
This effort is unique because it seeks to stimulate a pathway that can prevent an underlying cause of Parkinson’s disease. As of yet, there are no therapies that prevent the death of neurons in the brain associated with the disease progression. Clinical data have shown that PD patients have an increased number of damaged mitochondria.  By increasing mitochondrial health, we aim to prevent the death of dopaminergic neurons. 

Anticipated Outcome:          
We anticipate identifying therapeutically active molecules that increase the amount of parkin and ultimately protect cells from mitochondrial dysfunction. Based on previous results in models, we expect that increasing parkin will prevent the death of neurons. This will set the stage for developing entirely new drugs for Parkinson’s and clinical trials of drugs already approved for other diseases.

Final Outcome

We engineered a new cell model for selecting drugs with certain properties from a large number of potential candidates. We used the model to identify potential drug candidates capable of increasing the level of Parkin, a protein that prevents cell death by breaking down damaged mitochondria, cell's energy generators. Using this model, we screened over 350,000 drug candidates at five different doses each to find the most promising. We discovered several candidates that increase Parkin level. Importantly, two of them also improved the removal of damaged mitochondria from the cell. The next phase of this program is to chemically modify the lead drug candidates and to test them in pre-clinical models of Parkinson's disease.

Presentations & Publications
Hasson SA, Fogel AI, Wang C, et al. Chemogenomic profiling of endogenous PARK2 expression using a genome-edited coincidence reporter. ACS Chem Biol. 2015;10(5):1188-1197.


  • James Inglese, PhD

    Bethesda, MD United States

  • Richard J. Youle, PhD

    Bethesda, MD United States

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