Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity
Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity
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帕金森相关 LRRK2 突变 R1628P 使 LRRK2 的 Cdk5 磷酸化并上调其激酶活性
DOI：
10.1371/journal.pone.0149739
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发表时间：
2016-03-01
期刊：
影响因子：
3.7
通讯作者：
Tian, Bo
中科院分区：
文献类型：
--
作者：
Shu, Yang;Ming, Jie;Tian, Bo
背景研究表明富含亮氨酸重复序列激酶2（LRRK 2）基因的某些单核苷酸多态性与帕金森病（PD）有关。在这些突变中，LRRK 2 c.4883G>C（R1628 P）变异被鉴定为与汉族人群中的PD风险显著相关。主要发现与Roc-COR-Kinase结构域中的其他LRRK 2突变体不同，R1628 P突变并不改变LRRK 2激酶的活性并直接促进神经元死亡。LRRK 2 R1628 P突变增加了LRRK 2与细胞周期蛋白依赖性激酶5（Cdk 5）的结合亲和力。有趣的是，R1628 P突变将LRRK 2蛋白上相邻的氨基酸残基S1627变成Cdk 5的一个新的磷酸化位点，这可以被定义为典型的II型（+）磷酸化相关的单核苷酸多态性。重要的是，我们发现，磷酸化的S1627由Cdk 5可以激活LRRK 2激酶，和神经元异位表达R1628 P表现出更高的敏感性，1-甲基-4-苯基吡啶，一种生物活性代谢物的环境毒素MPTP，在Cdk 5依赖martens.ConclusionOur数据表明，帕金森病相关的LRRK 2突变R1628 P导致Cdk 5磷酸化的LRRK 2在S1627，其将上调LRRK 2的激酶活性并因此导致神经元死亡。
BackgroundRecent studies have linked certain single nucleotide polymorphisms in the leucine-rich repeat kinase 2 (LRRK2) gene with Parkinson's disease (PD). Among the mutations, LRRK2 c.4883G>C (R1628P) variant was identified to have a significant association with the risk of PD in ethnic Han-Chinese populations. But the molecular pathological mechanisms of R1628P mutation in PD is still unknown.Principle FindingsUnlike other LRRK2 mutants in the Roc-COR-Kinase domain, the R1628P mutation didn't alter the LRRK2 kinase activity and promote neuronal death directly. LRRK2 R1628P mutation increased the binding affinity of LRRK2 with Cyclin-dependent kinase 5 (Cdk5). Interestingly, R1628P mutation turned its adjacent amino acid residue S1627 on LRRK2 protein to a novel phosphorylation site of Cdk5, which could be defined as a typical type II (+) phosphorylation-related single nucleotide polymorphism. Importantly, we showed that the phosphorylation of S1627 by Cdk5 could activate the LRRK2 kinase, and neurons ectopically expressing R1628P displayed a higher sensitivity to 1-methyl-4-phenylpyridinium, a bioactive metabolite of environmental toxin MPTP, in a Cdk5-dependent manner.ConclusionOur data indicate that Parkinson-related LRRK2 mutation R1628P leads to Cdk5 phosphorylation of LRRK2 at S1627, which would upregulate the kinase activity of LRRK2 and consequently cause neuronal death.