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Human Molecular Genetics Advance Access originally published online on December 1, 2005
Human Molecular Genetics 2006 15(2):223-232; doi:10.1093/hmg/ddi439
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity

Christian Johannes Gloeckner1, Norbert Kinkl1,2, Annette Schumacher1, Ralf J. Braun1, Eric O'Neill3, Thomas Meitinger1,2, Walter Kolch3, Holger Prokisch1,2 and Marius Ueffing1,2,*

1GSF-National Research Center for Environment and Health, Institute of Human Genetics, Munich-Neuherberg, Germany, 2Institute of Human Genetics, Technical University Munich, Munich, Germany and 3The Beatson Institute for Cancer Research, Glasgow, UK

* To whom correspondence should be addressed at: GSF-National Research Center for Environment and Health, Institute of Human Genetics, Ingolstaedter Landstr. 1, 85764 Munich-Neuherberg, Germany. Tel: +49 8931873567; Fax: +49 8931874426; Email: marius.ueffing{at}gsf.de

Received September 17, 2005; Accepted November 25, 2005

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been recently identified in families with autosomal dominant late-onset Parkinson disease (PD). The LRRK2 protein consists of multiple domains and belongs to the Roco family, a novel group of the Ras/GTPase superfamily. Besides the GTPase (Roc) domain, it contains a predicted kinase domain, with homology to MAP kinase kinase kinases. Using cell fractionation and immunofluorescence microscopy, we show that LRRK2 is localized in the cytoplasm and is associated with cellular membrane structures. The purified LRRK2 protein demonstrates autokinase activity. The disease-associated I2020T mutant shows a significant increase in autophosphorylation of ~40% in comparison to wild-type protein in vitro. This suggests that the pathology of PD caused by the I2020T mutation is associated with an increase rather than a loss in LRRK2 kinase activity.


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