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. Ongoing work on this project is to map protein interactors particularly around the COR domain. We have some evidence now that there are functionally important co-chaperones that bind in this region. We have found that these interactions do allow the formation of a large protein complex that is stabilized by chaperones and has a novel function in autophagy. Mutations in the ROC and COR domains do affect this function but do not affect protein interactions. Ongoing work is aimed at understanding how the activities of LRRK2 impact complex function. We have also developed an approach to find novel modulators of LRRK2 function, initially via phosphorylation. We are currently trying to understand how this relates to cellular functions identified above.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Institute on Aging
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Langston, Rebekah G; Rudenko, Iakov N; Cookson, Mark R (2016) The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research. Biochem J 473:221-32
Cookson, Mark R (2015) LRRK2 Pathways Leading to Neurodegeneration. Curr Neurol Neurosci Rep 15:42
Civiero, Laura; Cirnaru, Maria Daniela; Beilina, Alexandra et al. (2015) Leucine-rich repeat kinase 2 interacts with p21-activated kinase 6 to control neurite complexity in mammalian brain. J Neurochem 135:1242-56
Reyniers, Lauran; Del Giudice, Maria Grazia; Civiero, Laura et al. (2014) Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways. J Neurochem 131:239-50
Law, Bernard M H; Spain, Victoria A; Leinster, Veronica H L et al. (2014) A direct interaction between leucine-rich repeat kinase 2 and specific *-tubulin isoforms regulates tubulin acetylation. J Biol Chem 289:895-908
Liao, Jingling; Wu, Chun-Xiang; Burlak, Christopher et al. (2014) Parkinson disease-associated mutation R1441H in LRRK2 prolongs the ""active state"" of its GTPase domain. Proc Natl Acad Sci U S A 111:4055-60
Rudenko, Iakov N; Chia, Ruth; Cookson, Mark R (2012) Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease? BMC Med 10:20
Taymans, Jean-Marc; Vancraenenbroeck, Renee; Ollikainen, Petri et al. (2011) LRRK2 kinase activity is dependent on LRRK2 GTP binding capacity but independent of LRRK2 GTP binding. PLoS One 6:e23207
Cookson, Mark R (2010) The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat Rev Neurosci 11:791-7
Rudenko, Iakov N; Cookson, Mark R (2010) 14-3-3 proteins are promising LRRK2 interactors. Biochem J 430:e5-6