Identification of Small Molecules that Stabilize Parkin in an Active Conformation

Objective/Rationale:
Parkin is a protein linked to hereditary, young-onset Parkinson’s disease (PD) through a series of genetic mutations. Its formal role in PD is not fully understood, but its activity has been shown to protect neurons from toxins that can lead to disease in patients and in pre-clinical models. In the cell, parkin is present but apparently inactive. This project seeks to identify small molecules that will increase the amount of active parkin in cells, which can protect neurons from PD-associated toxins. 

Project Description:
The molecular structure of parkin shows it exists in an inactive conformation, and a significant structural shift is expected to occur to achieve active protein. We will monitor the stability, activity and conformation of parkin in solution in the presence and absence of small fragments of drugs. Once we identify fragments that can activate parkin, we will continue to modify these molecules in search of potential therapeutic agents that can be tested in cells and pre-clinical models. 

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Models have demonstrated that parkin is neuroprotective to a number of toxins known to lead to PD. Identification of small molecules that can convert inactive parkin found in the cells to an active conformation may provide a therapeutic agent for protection of cells from further damage or potentially to reverse the damage in PD-affected cells.

Anticipated Outcome:
This study should yield small molecule activators of parkin. We will characterize the molecular structure of small molecule-activated Parkin and test these molecules in cells and pre-clinical models. This will allow us to develop a long-term strategy to identify small molecule activators that can lead to a therapeutic agent for PD.