Journal Article

Leucine-rich repeat kinase 2 associates with lipid rafts

Taku Hatano, Shin-ichiro Kubo, Satoshi Imai, Masahiro Maeda, Kiyoshi Ishikawa, Yoshikuni Mizuno and Nobutaka Hattori

in Human Molecular Genetics

Volume 16, issue 6, pages 678-690
Published in print March 2007 | ISSN: 0964-6906
Published online March 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm013
Leucine-rich repeat kinase 2 associates with lipid rafts

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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, Ras in complex proteins (Roc) followed by C-terminal of Roc (COR), 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 (WT). I2020T mutant LRRK2 associates with lipid rafts, similar to the WT. The lipid raft association of LRRK2 mutants as well as WT LRRK2 suggests that alteration of LRRK2 function on lipid rafts contributes to the pathogenesis of PD.

Journal Article.  6246 words.  Illustrated.

Subjects: Genetics and Genomics

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