Leucine rich repeat kinase 2 and dominantly inherited Parkinson disease

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Leucine rich repeat kinase 2 (LRRK2) mutations are causal for inherited Parkinsons disease with age-dependent penetrance. The protein is a large complex kinase with several reported protein interactions and mutliple proposed functions. Some mutations increase kinase activity, and the overall aim of this project is to extend our prior observations that kinase activity of LRRK2 is important in pathogenesis association with mutations in this gene. In the past reporting period, we have spent some time characterizing highly purified LRRK2 protein, and the related homolog LRRK1. We find that both proteins form dimers, which we had previously suggested but has been controversial. One possibility, which we are pursuing, is that there are protein binding partners and/or conformational states of LRRK2 that prevent this from happening within cells. We were also able to confirm our previous observations with partially purified material, that the Parkinson's disease associated LRRK2 protein is a more active kinase than the homolog LRRK1. The significance of this observation is not yet clear. We have also characterized a risk factor variant for LRRK2, G2385R, which we found surprisingly has lower kinase activity than wild type protein. The likely mechanism is that G2385R alters intramolecular interactions within the large, complex protein. This work may have implications for the types of therapeutics that should be developed for LRRK2-related disease.