Objective/Rationale:
Many genetic disorders are caused by the loss of a functional protein which protects cells from disease. These disorders are difficult to treat with drugs because most drugs block the function of a particular protein. This project seeks to rescue the activity of a mutant protein important in Parkinson’s disease. We have made a surprising discovery that the enzyme PINK1 in its Parkinson’s mutant form can be made active if we provide it with a designed non-natural substrate drug.
Project Description:
We now have solid biochemical evidence that our drug candidate can increase the function of the PINK1 kinase, which is important for neuronal survival in response to stress. We are now progressing to the critical stage of testing our drug candidate in human cells of both non-neuronal and neuronal types. We will be using microscopy and fluorescent proteins to visualize processes in the cells which are thought to be dependent upon PINK1 activity. Our experiments will be designed to test the structural requirements of our drug candidate for efficacy in neuronal protection. We will work to make a solid link between our drug candidate and the PINK1 enzyme—and show that by adding our rescue drug to neurons we can protect them from death in a PINK1-dependent manner.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If successful, I think it will open the door to a new therapy for Parkinson’s patients. A chemical which can rescue an inactive enzyme required for neuronal survival would be a very exciting medical advance. The ability to genotype patients and provide them a custom drug regimen would be particularly helpful because it would allow only the patients with a strong likelihood of benefiting from the drug to be given the drug. I want to stress again that this is a very risky approach but we are excited about the opportunity to explore it vigorously.
Anticipated Outcome:
We hope to provide robust and comprehensive cellular data on a new potential drug to treat Parkinson’s disease. The strategy we are taking is risky and really unprecedented but we have solid evidence in simplified systems that we can increase the function of a neuroprotective kinase, PINK1, strongly implicated in Parkinson’s disease. If the proposed work is successful, we will be in a position to test our molecules in pre-clinical models.