Caenorhabditits elegans LRK-1 and PINK-1 Act Antagonistically in Stress Response and Neurite Outgrowth
Caenorhabditits elegans LRK-1 and PINK-1 Act Antagonistically in Stress Response and Neurite Outgrowth
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DOI：
10.1074/jbc.m808255200
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发表时间：
2009-06-12
影响因子：
4.8
通讯作者：
Schmidt, Enrico
中科院分区：
文献类型：
--
作者：
Saermann, Julia;Hegermann, Jan;Schmidt, Enrico
编码假定激酶LRRK 2和PINK 1的两个基因的突变与帕金森病的遗传变异有关。这两种蛋白质的生理作用目前尚不清楚，但在模式生物中的研究已经将它们的突变体与线粒体功能障碍的不同方面联系起来，增加了对氧化和内质网应激的脆弱性，以及细胞内蛋白质分选。在这里，我们表明，突变的秀丽隐杆线虫同源的PTEN诱导的激酶粉红色-1基因导致线粒体嵴长度减少和百草枯敏感性增加的线虫。此外，突变体还显示出一对神经管相关神经元轴突生长的缺陷。我们证明，在缺乏lrk-1的情况下，C. elegans同源的人LRRK 2，所有的表型方面的粉红色-1功能丧失突变体被抑制。相反，lrk-1突变体动物对内质网应激子衣霉素的超敏反应在pink-1突变体背景下降低。这些结果提供了PINK-1和LRK-1拮抗作用的第一个证据。由于C. elegans蛋白与人LRRK 2和PINK 1的关系，我们认为这两种因子在细胞功能中的共同作用，包括应激反应和神经突生长的调节。这项研究可能有助于将pink-1/PINK 1和lrk-1/LRRK 2功能与帕金森病相关基因突变引起的病理过程联系起来，这些突变的第一个表现是受影响神经元的细胞骨架缺陷。
Mutations in two genes encoding the putative kinases LRRK2 and PINK1 have been associated with inherited variants of Parkinson disease. The physiological role of both proteins is not known at present, but studies in model organisms have linked their mutants to distinct aspects of mitochondrial dysfunction, increased vulnerability to oxidative and endoplasmic reticulum stress, and intracellular protein sorting. Here, we show that a mutation in the Caenorhabditits elegans homologue of the PTEN-induced kinase pink-1 gene resulted in reduced mitochondrial cristae length and increased paraquat sensitivity of the nematode. Moreover, the mutants also displayed defects in axonal outgrowth of a pair of canal-associated neurons. We demonstrate that in the absence of lrk-1, the C. elegans homologue of human LRRK2, all phenotypic aspects of pink-1 loss-of-function mutants were suppressed. Conversely, the hypersensitivity of lrk-1 mutant animals to the endoplasmic reticulum stressor tunicamycin was reduced in a pink-1 mutant background. These results provide the first evidence of an antagonistic role of PINK-1 and LRK-1. Due to the similarity of the C. elegans proteins to human LRRK2 and PINK1, we suggest a common role of both factors in cellular functions including stress response and regulation of neurite outgrowth. This study might help to link pink-1/PINK1 and lrk-1/LRRK2 function to the pathological processes resulting from Parkinson disease-related mutants in both genes, the first manifestations of which are cytoskeletal defects in affected neurons.