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Human Molecular Genetics Advance Access published online on December 1, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi439
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 17, 2005
Accepted November 25, 2005

Article

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

Christian Johannes Gloeckner 1, Norbert Kinkl 2, Annette Schumacher 1, Ralf J. Braun 1, Eric O'Neill 3, Thomas Meitinger 2, Walter Kolch 3, Holger Prokisch 2, and Marius Ueffing 4 *

1 GSF-National Research Center for Environment and Health, Institute of Human Genetics, Munich-Neuherberg, Germany
2 GSF-National Research Center for Environment and Health, Institute of Human Genetics, Munich-Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, Munich, Germany
3 The Beatson Institute for Cancer Research, Glasgow, UK
4 GSF-National Research Center for Environment and Health, Institute of Human Genetics, Ingolstaedter Landstr. 1, 85764, Munich-Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, Munich, Germany

* To whom correspondence should be addressed.
Marius Ueffing, E-mail: marius.ueffing{at}gsf.de


  Abstract

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 (MAPKKK). Using cell fractionation and immunofluorescence microscopy we show that LRRK2 is localised 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 about 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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