Promising Outcomes of Original Grant:
Our original grant focused on determining the structure of the complex formed by the Parkinson’s-associated protein beta-gluccocerebrosidase (GCase) and its transporter LIMP-2. About seven to 12 percent of Parkinson’s patients carry mutations in the gene encoding for GCase. The two proteins LIMP-2 and GCase meet in the cell and then travel together to the lysosome, a cellular compartment important for cellular waste removal. In previous work, we found that LIMP-2 can increase GCase activity. After determining the structure of this protein complex we want to utilize the contact site for the design of a GCase activator. Activators for GCase are promising candidates for clinical intervention in Parkinson’s patients. Some activators for GCase are in clinical trials right now.
Objectives for Supplemental Investigation:
In the proposed project we will also include GCase variants associated with Parkinson’s. Therefore, we will use LIMP-2 as a tool to harvest GCase from cell culture and use different biochemical methods to test the complex properties. We were also able to determine a preliminary structure of the complex and in this project, we will continue our investigation on this matter. We will also include the Parkinson’s-associated variants into our structural project. Structures of these Parkinson’s-associated protein complexes will eventually shed light on how the mutations influence complex stability and thereby enzymatic activity of GCase.
Importance of This Research for the Development of a New PD Therapy:
As LIMP-2 increases GCase activity, exact understanding of the interaction site will open new doors for the development of GCase activators.