Journal Article

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

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

in Human Molecular Genetics

Volume 15, issue 2, pages 223-232
Published in print January 2006 | ISSN: 0964-6906
Published online December 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi439
The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity

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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.

Journal Article.  6171 words.  Illustrated.

Subjects: Genetics and Genomics

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