Promising Outcomes of Original Grant:
We were trying to understand how the PINK1 gene targets a set of proteins known as Rab GTPases through protein modification known as phosphorylation. The highlight of our studies was the discovery that boosting PINK1-induced phosphorylation of Rab8A may have therapeutic potential by dampening another Parkinson’s gene known as LRRK2, which also targets Rab GTPases. This involved the successful generation of the modified/phosphorylated Rab protein and the development of a powerful antibody tool to track Rab phosphorylation by PINK1 in cells.
Objectives for Supplemental Investigation:
Our studies have highlighted that another enzyme directly targets the Rab GTPases once PINK1 is activated. We will perform a genetic screen to uncover the identity of this enzyme and test its ability to directly target Rab GTPases and determine how its function is controlled by PINK1.
Importance of This Research for the Development of a New PD Therapy:
Our studies so far suggest that targeting this unknown enzyme is likely to offer a potential therapeutic strategy to dampen the activity of the LRRK2 protein in patients with LRRK2 hyper-activating mutations.