Study Rationale:
Defects in the protein parkin cause the loss of nerve cells in the brain and are responsible for many cases of young-onset Parkinson’s disease that develops before 50 years of age. We now understand how Parkin normally needs to change its shape to function, and how this fails to occur in patients with defects in this protein. We aim to generate chemicals that provoke defective parkin to change shape and re-activate it and to establish new drugs to treat young-onset Parkinson’s disease.

Hypothesis:
Some defective forms of parkin protein can be reactivated with chemicals.

Study Design:
We will design an assay (laboratory test) to monitor how the purified parkin protein changes its shape when it is activated. We will then use this assay to screen several hundred thousand chemicals to identify those that can provoke parkin to undergo this shape change. These chemicals will be further tested in cells and in models that are engineered to express defective forms of parkin.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
If successful, chemical activators of parkin could treat patients with young-onset Parkinson’s disease in whom parkin activation is stalled. Our innovative drug discovery program provides the rare opportunity to advance personalized medicine to a defined patient population.

Next Steps for Development:
Identified chemicals will require medicinal chemistry efforts to optimize drug-like properties, efficacy and efficient delivery.

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