Our main aim in this project is to understand how mutations across many different domains of LRRK2 cause dominantly inherited Parkinsons disease. We previously reported that there was a diminishment of kinase function by a risk factor variant in LRRK2, G2385R. We know now that, mechanistically, the mutant version of LRRK2 is unstable likely due to misfolding at the C-terminus that promotes binding of chaperones. As this event is separated physically from the kinase domain, our working hypothesis is that the C-terminus and kinase domains interact with each other. We are currently extending this work to examine whether loss of function is also seen in the mouse version of the protein, which would allow us to test the idea of loss of function in vivo using knockin mice.

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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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
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
Mamais, Adamantios; Cookson, Mark R (2014) LRRK2: dropping (kinase) inhibitions and seeking an (immune) response. J Neurochem 129:895-7
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
Rudenko, Iakov N; Cookson, Mark R (2014) Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications. Neurotherapeutics :
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
Hsu, Cindy H; Chan, Diane; Greggio, Elisa et al. (2010) MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2. J Neurochem 112:1593-604
Saha, Shamol; Guillily, Maria D; Ferree, Andrew et al. (2009) LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J Neurosci 29:9210-8
Greggio, Elisa; Cookson, Mark R (2009) Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. ASN Neuro 1:
Cookson, Mark R; Hardy, John; Lewis, Patrick A (2008) Genetic neuropathology of Parkinson's disease. Int J Clin Exp Pathol 1:217-31