Leucine-rich repeat kinase 2 (LRRK2) is a complex protein with multiple protein-protein interaction domains and two enzymatic activities. Several previous studies have suggested that the kinase activity of LRRK2 is linked to binding of guanosine nucleotides and, hence, to its GTPase activity. Dominant mutations in the LRRK2 gene cause inherited PD with variable neuropathology and mutations either increase kinase activity or decrease GTPase activity. All mutations are toxic at least in cell culture models, again implying that the two activities are functionally linked to pathogenic outcomes. However, the molecular details of how LRRK2 mutations impact protein function and hence neuronal viability are unclear. We have been particularly interested in how all the mutations in LRRK2, spread around different protein domains, lead to a very similar phenotype as this commonality is likely the critical underlying reason for why LRRK2 causes disease. To address this, we and others have been examining potential substrates for the LRRK2 kinase activity. In our own hands, most of the substrates proposed to this point are actually relatively poor, only accepting small amounts of phosphorylation when present at large molar excess to the enzyme. In contrast, under the same conditions, LRRK2 phosphorylates itself relatively well. We have previously shown that this is largely an intramolecular reaction, at least limited to within a given dimer pair for LRRK2. To try and understand why autophosphorylation occurs, we have mapped the reaction within LRRK2. Surprisingly, we find that LRRK2 can phosphorylate its own GTP-binding region, implying that there is a complex set of autoregulatory reactions for this protein. Future work will be directed at understanding whether such reactions occur under physiological conditions. We have also been involved in identifying how LRRK2 modifies responses to a variety of stimuli. We have found that LRRK2 can alter responses to stressful stimuli, including mitochondrial toxins, in a worm model. This suggests in a broad sense that the role of LRRK2 is normally to maintain neuronal integrity over time and that mutations negatively impact this function. Future work will be directed at confirming this result in different systems.