Leucine-rich repeat kinase 2 induces α-synuclein expression via the extracellular signal-regulated kinase pathway
Leucine-rich repeat kinase 2 induces α-synuclein expression via the extracellular signal-regulated kinase pathway
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DOI：
10.1016/j.cellsig.2010.01.006
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发表时间：
2010-05-01
影响因子：
4.8
通讯作者：
Kahle, Philipp J.
中科院分区：
文献类型：
--
作者：
Carballo-Carbajal, Iria;Weber-Endress, Susanne;Kahle, Philipp J.
富含亮氨酸重复序列激酶2（LRRK 2）的突变是常染色体显性帕金森病（PD）的最常见原因。第二个已知的常染色体显性PD基因（SNCA）编码α-突触核蛋白，其沉积在路易体中，这是PD的神经病理学标志。LRRK 2含有与促分裂原活化蛋白激酶（MAPKKKs）同源的激酶结构域，并且其活性已被认为是LRRK 2相关PD中的关键因子。在这里，我们研究了LRRK 2在信号转导通路中的作用，以确定推定的PD相关下游靶点。在人胚肾HEK 293细胞中过表达野生型[wt] LRRK 2选择性地激活细胞外信号调节激酶（ERK）模块。PD相关突变体G2019 S和R1441 C（而非激酶死亡的LRRK 2）诱导ERK磷酸化的程度与[wt] LRRK 2相同，表明这种作用是激酶依赖性的。然而，突变体R1441 C和G2019 S的ERK激活明显慢于[wt] LRRK 2，尽管表达水平相似。此外，通过LRRK 2对ERK模块的诱导与SNCA的小但显著的诱导相关，SNCA的诱导通过用选择性MAPK/ERK激酶抑制剂U 0126处理而被抑制。这种连接两个显性PD基因LRRK 2和SNCA的途径可能为家族性和散发性疾病的药物治疗提供一个有趣的靶点。(C)2010年爱思唯尔公司All rights reserved.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of autosomal-dominant Parkinson's disease (PD). The second known autosomal-dominant PD gene (SNCA) encodes a-synuclein, which is deposited in Lewy bodies, the neuropathological hallmark of PD. LRRK2 contains a kinase domain with homology to mitogen-activated protein kinase kinase kinases (MAPKKKs) and its activity has been suggested to be a key factor in LRRK2-associated PD. Here we investigated the role of LRRK2 in signal transduction pathways to identify putative PD-relevant downstream targets. Over-expression of wild-type [wt]LRRK2 in human embryonic kidney HEK293 cells selectively activated the extracellular signal-regulated kinase (ERK) module. PD-associated mutants G2019S and R1441C, but not kinase-dead LRRK2, induced ERK phosphorylation to the same extent as [wt]LRRK2, indicating that this effect is kinase-dependent. However, ERK activation by mutant R1441C and G2019S was significantly slower than that for [wt]LRRK2, despite similar levels of expression. Furthermore, induction of the ERK module by LRRK2 was associated to a small but significant induction of SNCA, which was suppressed by treatment with the selective MAPK/ERK kinase inhibitor U0126. This pathway linking the two dominant PD genes LRRK2 and SNCA may offer an interesting target for drug therapy in both familial and sporadic disease. (C) 2010 Elsevier Inc. All rights reserved.