Department of Biology, McGill University Health Centre, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada.
Mol Brain. 2011 Apr 19;4:17. doi: 10.1186/1756-6606-4-17.
Mutations in parkin and PTEN-induced kinase 1 (Pink1) lead to autosomal recessive forms of Parkinson's disease (PD). parkin and Pink1 encode a ubiquitin-protein ligase and a mitochondrially localized serine/threonine kinase, respectively. Recent studies have implicated Parkin and Pink1 in a common and evolutionarily conserved pathway for protecting mitochondrial integrity.
To systematically identify novel components of the PD pathways, we generated a genetic background that allowed us to perform a genome-wide F1 screen for modifiers of Drosophila parkin (park) and Pink1 mutant phenotype. From screening ~80% of the fly genome, we identified a number of cytological regions that interact with park and/or Pink1. Among them, four cytological regions were selected for identifying corresponding PD-interacting genes. By analyzing smaller deficiency chromosomes, available transgenic RNAi lines, and P-element insertions, we identified five PD-interacting genes. Among them, opa1 and drp1 have been previously implicated in the PD pathways, whereas debra (dbr), Pi3K21B and β4GalNAcTA are novel PD-interacting genes.
We took an unbiased genetic approach to systematically isolate modifiers of PD genes in Drosophila. Further study of novel PD-interacting genes will shed new light on the function of PD genes and help in the development of new therapeutic strategies for treating Parkinson's disease.
Parkin 和 PTEN 诱导激酶 1 (Pink1) 的突变导致常染色体隐性形式的帕金森病 (PD)。Parkin 和 Pink1 分别编码泛素蛋白连接酶和定位于线粒体的丝氨酸/苏氨酸激酶。最近的研究表明 Parkin 和 Pink1 在保护线粒体完整性的一个共同的和进化上保守的途径中起作用。
为了系统地鉴定 PD 途径的新组分，我们构建了一个遗传背景，使我们能够进行全基因组 F1 筛选，以寻找果蝇 parkin (park) 和 Pink1 突变表型的修饰因子。通过筛选约 80%的基因组，我们鉴定了一些与 park 和/或 Pink1 相互作用的细胞学区域。其中，四个细胞学区域被选择用于鉴定相应的 PD 相互作用基因。通过分析较小的缺失染色体、可用的转基因 RNAi 系和 P 元素插入，我们鉴定了五个 PD 相互作用基因。其中，opa1 和 drp1 先前已被认为与 PD 途径有关，而 debra (dbr)、Pi3K21B 和 β4GalNAcTA 是新的 PD 相互作用基因。
我们采用了一种无偏的遗传方法，系统地分离了果蝇 PD 基因的修饰因子。对新的 PD 相互作用基因的进一步研究将揭示 PD 基因的功能，并有助于开发治疗帕金森病的新治疗策略。
