Study Rationale:
Parkinson's disease is characterized by a loss of nerve cells (neurons) in the brain resulting potentially from their inability to remove damaged mitochondria, which control energy production. In people with Parkinson's disease, damaged mitochondria accumulate and may contribute to the death of neurons. Parkin, an enzyme that promotes protein degradation, can help remove damaged mitochondria from the neurons, but it must be activated in these neurons to work. In this project, small molecules than can activate Parkin will be identified and developed into drugs that can treat Parkinson's disease by eliminating damaged mitochondria and preserving neuronal health.
Hypothesis:
The first phase of the study will determine the feasibility of identifying small molecules that can both activate the enzyme parkin selectively and function in various neuronal cell models to improve the clearance of damaged mitochondria in a way that would benefit people with Parkinson's disease.
Study Design:
Using a robotics system that tests thousands of compounds daily, each of 600,000 small molecules will be tested for its ability to activate parkin but not related enzymes. Next, molecules that activate parkin will be tested in living cells to see whether they activate parkin without harming the cells. The structures of safe and active molecules will be examined to see whether they are suitable for drug development, and, finally, those compounds that pass these tests will be evaluated to see whether they can increase the ability of cells to remove damaged mitochondria.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Current treatments for Parkinson's do not treat the underlying causes of neurodegeneration. A successful drug that removes damaged mitochondria may prevent neuronal degeneration and progression of Parkinson's disease and therefore represent an advance in the way this disease is treated.
Next Steps for Development:
Compounds passing the various studies in this project will be modified by chemical alteration of their structures to turn them into molecules with improved activity and properties that are suitable for administering orally to patients. The best of these chemically modified molecules will then be evaluated in models and developed as therapies for Parkinson's disease.