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.

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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Cookson, Mark R (2016) Cellular functions of LRRK2 implicate vesicular trafficking pathways in Parkinson's disease. Biochem Soc Trans 44:1603-1610
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
West, Andrew B; Cookson, Mark R (2016) Identification of bona-fide LRRK2 kinase substrates. Mov Disord 31:1140-1
Cookson, Mark R (2016) Structure, function, and leucine-rich repeat kinase 2: On the importance of reproducibility in understanding Parkinson's disease. Proc Natl Acad Sci U S A 113:8346-8
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
Beilina, Alexandra; Cookson, Mark R (2015) Genes associated with Parkinson's disease: regulation of autophagy and beyond. J Neurochem :
Beilina, Alexandria; Rudenko, Iakov N; Kaganovich, Alice et al. (2014) Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proc Natl Acad Sci U S A 111:2626-31
Skibinski, Gaia; Nakamura, Ken; Cookson, Mark R et al. (2014) Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. J Neurosci 34:418-33
Mamais, Adamantios; Chia, Ruth; Beilina, Alexandra et al. (2014) Arsenite stress down-regulates phosphorylation and 14-3-3 binding of leucine-rich repeat kinase 2 (LRRK2), promoting self-association and cellular redistribution. J Biol Chem 289:21386-400
Rudenko, Iakov N; Cookson, Mark R (2014) Heterogeneity of leucine-rich repeat kinase 2 mutations: genetics, mechanisms and therapeutic implications. Neurotherapeutics 11:738-50

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