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Human Molecular Genetics Advance Access published online on March 6, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm013
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Leucine-rich repeat kinase 2 associates with lipid rafts

Taku Hatano1, Shin-ichiro Kubo1, Satoshi Imai1, Masahiro Maeda3, Kiyoshi Ishikawa3, Yoshikuni Mizuno2 and Nobutaka Hattori1,2,*

1 Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan 2 Research Institute for Diseases of Old Age, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan 3 Immuno-Biological Laboratories Co., Ltd, 1091-1 Naka, Fujioka, Gunma 375-0005, Japan

* Correspondence should be addressed to Prof. N. H. Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan, Phone: +81-3-3813-3111, Fax: +81-3-5684-0476, E-mail: nhattori{at}med.juntendo.ac.jp

Received November 7, 2006; Revised January 5, 2007; Accepted February 2, 2007

Leucine-Rich Repeat Kinase 2 (LRRK2) is a causative gene for the autosomal dominant form of Parkinson's disease (PD). The gene encodes the ~280 kDa LRRK2 protein composed of domains such as leucine-rich repeats, Roc (Ras in complex proteins) followed by COR (C-terminal of Roc), mitogen-activated protein kinase kinase kinase (MAPKKK), and WD40. However, the normal function of the protein as well as its contribution to the pathogenesis of PD remains largely unknown. Here we describe the localization of LRRK2 in Golgi apparatus, plasma membrane, and synaptic vesicles in cultured cells including mouse primary neurons. The membrane association of LRRK2 resists solubilization by ice-cold 1% Triton X-100, indicating its association through lipid rafts. To investigate whether mutations found in PD patients affect the localization of LRRK2, we transfected various LRRK2 mutants into cultured cells and performed fractionation experiments. Unexpectedly, the mutants are collected in both membrane and soluble fractions in a manner similar to wild-type. I2020T mutant LRRK2 associates with lipid rafts, similar to the wild-type. The lipid raft association of LRRK2 mutants as well as wild-type LRRK2 suggests that alteration of LRRK2 function on lipid rafts contributes to the pathogenesis of PD.


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