LRRK2 gene mutations are a common cause of Parkinsons disease. The protein product of the gene has both kinase and GTPase activities. Because there are mutations in both kinase and GTPase domains, we consider that both activities are probably important for pathogenesis of Parkinsons disease. As such, we are trying to understand each activity in turn and how they interact. In the current period, we have extended previous observations that show that mutations within the ROC-COR bidomain, which is where GTP binding and hydrolysis occurs within the LRRK2 molecule, are associated with lower GTPase activity. Mechanistically, we were able to show that this effect is seen with protein preparations that appear to be predominantly monomeric and that the effect of mutation is to extend the active state of the protein. This has implications for how a detrimental mutation that causes a diminished function might be associated with a dominant disease. We have also extended our previous work looking at proteins that interact with this region of LRRK2. Several published studies have suggested that part of the pathogenic effects of LRRK2 mutations are mediated by changes in the cytoskeleton, specifically with microtubules. We have shown that LRRK2 interacts with specific tubulin isoforms in a number of different contexts.
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