Leucine-rich repeat kinase 2 associates with lipid rafts
Leucine-rich repeat kinase 2 associates with lipid rafts
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DOI：
10.1093/hmg/ddm013
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发表时间：
2007-03-15
影响因子：
3.5
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
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作者：
Hatano, Taku;Kubo, Shin-ichiro;Hattori, Nobutaka
富含亮氨酸重复激酶 2 (LRRK2) 是常染色体显性帕金森病 (PD) 的致病基因。该基因编码类似于 280 kDa LRRK2 蛋白，由富含亮氨酸重复序列、复杂蛋白 (Roc) 中的 Ras 以及随后的 Roc C 端 (COR)、丝裂原激活蛋白激酶激酶 (MAPKKK) 和 WD40 等结构域组成。然而，该蛋白的正常功能及其对帕金森病发病机制的贡献仍然很大程度上未知。在这里，我们描述了 LRRK2 在培养细胞（包括小鼠原代神经元）的高尔基体、质膜和突触小泡中的定位。 LRRK2 的膜结合可抵抗冰冷的 1% Triton X-100 的溶解，表明其通过脂筏进行结合。为了研究在PD患者中发现的突变是否影响LRRK2的定位，我们将各种LRRK2突变体转染到培养细胞中并进行分级实验。出乎意料的是，突变体以类似于野生型 (WT) 的方式收集在膜和可溶部分中。 I2020T 突变体 LRRK2 与脂筏相关，与 WT 类似。 LRRK2 突变体以及 WT LRRK2 的脂筏关联表明 LRRK2 在脂筏上功能的改变有助于 PD 的发病机制。
Leucine-Rich Repeat Kinase 2 (LRRK2) is a causative gene for the autosomal dominant form of Parkinson's disease (PD). The gene encodes the similar to 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.