Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin
Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin
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DOI：
10.1038/nature04788
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发表时间：
2006-06-28
期刊：
影响因子：
64.8
通讯作者：
Chung, Jongkyeong
中科院分区：
文献类型：
--
作者：
Park, Jeehye;Lee, Sung Bae;Chung, Jongkyeong
常染色体隐性青少年型帕金森病（AR - JP）是帕金森病的一种早发型，以运动障碍和多巴胺能神经变性为特征（1,2）。为了探究其潜在的分子发病机制，我们构建并鉴定了果蝇PTEN诱导的假定激酶1（PINK1）（3）的功能缺失突变体，PINK1是一个新的与AR - JP相关的基因（4）。在此，我们发现PINK1突变体表现出间接飞行肌和多巴胺能神经元变性，并伴有运动缺陷。此外，透射电子显微镜分析以及用果蝇Bcl - 2进行的挽救实验表明，线粒体功能障碍是PINK1突变体所有表型退行性变化的原因。值得注意的是，我们还发现PINK1突变体与parkin突变体具有显著的表型相似性。Parkin的转基因表达显著改善了所有PINK1功能缺失的表型，但反之则不然，这表明Parkin在PINK1的下游发挥作用。综上所述，我们的遗传学证据明确证实，Parkin和PINK1在维持肌肉和多巴胺能神经元的线粒体完整性和功能方面作用于同一通路。
Autosomal recessive juvenile parkinsonism (AR-JP) is an earlyonset form of Parkinson's disease characterized by motor disturbances and dopaminergic neurodegeneration(1,2). To address its underlyingmolecular pathogenesis, we generated and characterized loss-of-function mutants of Drosophila PTEN-induced putative kinase 1 (PINK1)(3), a novel AR-JP-linked gene(4). Here, we show that PINK1 mutants exhibit indirect flight muscle and dopaminergic neuronal degeneration accompanied by locomotive defects. Furthermore, transmission electron microscopy analysis and a rescue experiment with Drosophila Bcl-2 demonstrated that mitochondrial dysfunction accounts for the degenerative changes in all phenotypes of PINK1 mutants. Notably, we also found that PINK1 mutants share marked phenotypic similarities with parkin mutants. Transgenic expression of Parkin markedly ameliorated all PINK1 loss-of-function phenotypes, but not vice versa, suggesting that Parkin functions downstream of PINK1. Taken together, our genetic evidence clearly establishes that Parkin and PINK1 act in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons.