Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila
Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila
复制标题
DOI：
10.1038/emboj.2008.163
复制
发表时间：
2008-09-17
期刊：
影响因子：
11.4
通讯作者：
Lu, Bingwei
中科院分区：
文献类型：
--
作者：
Imai, Yuzuru;Gehrke, Stephan;Lu, Bingwei
富含亮氨酸的重复蛋白激酶2(LRRK2)的显性突变是迄今为止在帕金森病(PD)中发现的最常见的分子损伤。帕金森病是一种影响多巴胺(DA)神经元的年龄依赖性神经退行性疾病。LRRK2基因突变导致帕金森病患者DA变性的分子机制尚不清楚。在这里，我们发现人类LRRK2和果蝇LRRK2的同源物都能磷酸化真核细胞起始因子4E(EIF4E)结合蛋白(4E-BP)，它是eIF4E介导的蛋白质翻译的负调控因子，也是各种应激反应的关键介质。尽管LRRK2调节eIF4E/4E-BP通路在体内和体外都能刺激eIF4E介导的蛋白质翻译，但它减弱了果蝇DA神经元对氧化应激的抵抗和存活。我们的结果表明，具有致病突变的LRRK2对4E-BP的慢性失活会放松对蛋白质翻译的调控，最终导致DA神经元的年龄相关性损失。
Dominant mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent molecular lesions so far found in Parkinson's disease (PD), an age-dependent neurodegenerative disorder affecting dopaminergic (DA) neuron. The molecular mechanisms by which mutations in LRRK2 cause DA degeneration in PD are not understood. Here, we show that both human LRRK2 and the Drosophila orthologue of LRRK2 phosphorylate eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP), a negative regulator of eIF4E-mediated protein translation and a key mediator of various stress responses. Although modulation of the eIF4E/4E-BP pathway by LRRK2 stimulates eIF4E-mediated protein translation both in vivo and in vitro, it attenuates resistance to oxidative stress and survival of DA neuron in Drosophila. Our results suggest that chronic inactivation of 4E-BP by LRRK2 with pathogenic mutations deregulates protein translation, eventually resulting in age-dependent loss of DA neurons.