Towards a unifying theory of Parkinson's disease: Investigation of the biochemical and genetic role of Rab GTPases

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Mutations in the LRRK2 and PINK1 genes can be inherited in patients with familial forms of Parkinson's. LRRK2 and PINK1 function as a special class of enzymes known as protein kinases whose job is to label target proteins with a chemical phosphate group (in a process known as phosphorylation). Our laboratories have previously made significant advances in understanding the function of LRRK2 and PINK1 and recently identified that these enzymes target a different class of enzymes known as Rab GTPases. We now wish to better understand how LRRK2 and PINK1 controls Rabs and how mutations in these enzymes impact on Rab functioning in cells. Towards this goal we aim to identify the key Rabs controlled by LRRK2 and PINK1 and discover the molecules that Rabs bind to in order to execute downstream communications in the cell. To complement our analysis we will collaborate with genetics researchers to determine if Rabs themselves are mutated in families with Parkinson's. This project will lead to a fundamental understanding of the cellular pathways controlled by LRRK2 and PINK1 and improve our understanding of the critical pathways affected in Parkinson's.