Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin
Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin
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DOI：
10.1038/nature04779
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发表时间：
2006-06-28
期刊：
影响因子：
64.8
通讯作者：
Guo, Ming
中科院分区：
文献类型：
--
作者：
Clark, Ira E.;Dodson, Mark W.;Guo, Ming
帕金森氏病是第二个最常见的神经退行性疾病，其特征是黑质中多巴胺能神经元的变性。线粒体功能障碍已被认为是帕金森氏病样发病机理的重要触发因素，因为暴露于环境线粒体毒素会导致帕金森氏病的病理学（1）。最近，已经确定了介导家族性帕金森氏病的多种基因，包括PTEN诱导的激酶1（Pink1; Park6）和Parkin（Park2），它们也与零星形式的帕金森氏病（2-6）有关。 Pink1用线粒体靶向序列编码推定的丝氨酸/苏氨酸激酶（2）。到目前为止，在任何模型系统中尚未报告PINK1的体内研究。在这里，我们表明去除果蝇Pink1同源物（CG4523;以后称为Pink1）功能导致男性无菌性，凋亡肌肉变性，线粒体形态的缺陷以及对包括氧化应激（包括氧化应激）的多种应激的敏感性。 pink1定位于线粒体，线粒体crista在粉红色1突变体中分散。果蝇睾丸中人类Pink1的表达恢复了一部分Pink1突变体中男性的生育能力和正常的线粒体形态，表明了人与果蝇Pink1之间的功能保护。果蝇parkin的损失显示出类似于PINK1功能丧失的表型（7,8）。值得注意的是，帕金的过表达挽救了粉红色突变体的雄性不育和线粒体形态缺陷，而双突变体除去pink1和parkin功能都显示出与单独在任何一个突变体中观察到的肌肉表型相同的肌肉表型。这些观察结果表明，Pink1和Parkin的功能至少部分在同一途径中，Pink1在Parkin上游功能。 Pink1-Parkin途径在调节线粒体功能中的作用强调了线粒体功能障碍作为帕金森氏病发病机理的中心机制的重要性。
Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology(1). Recently, multiple genes mediating familial forms of Parkinson's disease have been identified, including PTEN-induced kinase 1 (PINK1; PARK6) and parkin (PARK2), which are also associated with sporadic forms of Parkinson's disease(2-6). PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence(2). So far, no in vivo studies have been reported for pink1 in any model system. Here we show that removal of Drosophila PINK1 homologue (CG4523; hereafter called pink1) function results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress. Pink1 localizes to mitochondria, and mitochondrial cristae are fragmented in pink1 mutants. Expression of human PINK1 in the Drosophila testes restores male fertility and normal mitochondrial morphology in a portion of pink1 mutants, demonstrating functional conservation between human and Drosophila Pink1. Loss of Drosophila parkin shows phenotypes similar to loss of pink1 function(7,8). Notably, overexpression of parkin rescues the male sterility and mitochondrial morphology defects of pink1 mutants, whereas double mutants removing both pink1 and parkin function show muscle phenotypes identical to those observed in either mutant alone. These observations suggest that pink1 and parkin function, at least in part, in the same pathway, with pink1 functioning upstream of parkin. The role of the pink1-parkin pathway in regulating mitochondrial function underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson's disease pathogenesis.