Pesah Yakov, Pham Tuan, Burgess Heather, Middlebrooks Brooke, Verstreken Patrik, Zhou Yi, Harding Mark, Bellen Hugo, Mardon Graeme
Division of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Development. 2004 May;131(9):2183-94. doi: 10.1242/dev.01095. Epub 2004 Apr 8.
Mutations in the gene parkin in humans (PARK2) are responsible for a large number of familial cases of autosomal-recessive Parkinson disease. We have isolated a Drosophila homolog of human PARK2 and characterized its expression and null phenotype. parkin null flies have 30% lower mass than wild-type controls which is in part accounted for by a reduced cell size and number. In addition, these flies are infertile, show significantly reduced longevity, and are unable to jump or fly. Rearing mutants on paraquat, which generates toxic free radicals in vivo, causes a further reduction in longevity. Furthermore, loss of parkin results in progressive degeneration of most indirect flight muscle (IFM) groups soon after eclosion, accompanied by apoptosis. However, parkin mutants have normal neuromuscular junction recordings during the third larval instar stage, suggesting that larval musculature is intact and that parkin is required only in pupal and adult muscle. parkin flies do not show an age-dependent dopaminergic neuron loss in the brain, even after aging adults for 3 weeks. Nevertheless, degeneration of IFMs demonstrates the importance of parkin in maintaining specific cell groups, perhaps those with a high-energy demand and the concomitant production of high levels of free radicals. parkin mutants will be a valuable model for future analysis of the mechanisms of cell and tissue degeneration.
人类基因parkin（PARK2）中的突变是导致大量常染色体隐性帕金森病家族病例的原因。我们分离出了人类PARK2的果蝇同源物，并对其表达和无效表型进行了表征。parkin基因缺失的果蝇比野生型对照果蝇体重低30%，这部分是由于细胞大小和数量减少所致。此外，这些果蝇不育，寿命显著缩短，无法跳跃或飞行。在百草枯上饲养突变体，百草枯在体内产生有毒自由基，会导致寿命进一步缩短。此外，parkin缺失会导致羽化后不久大多数间接飞行肌（IFM）组逐渐退化，并伴有细胞凋亡。然而，parkin突变体在第三龄幼虫阶段的神经肌肉接头记录正常，这表明幼虫肌肉组织完好无损，parkin仅在蛹期和成虫期的肌肉中发挥作用。即使将成年果蝇饲养3周后，parkin果蝇大脑中也未出现与年龄相关的多巴胺能神经元损失。尽管如此，IFM的退化证明了parkin在维持特定细胞群方面的重要性，这些细胞群可能是那些对能量需求高且伴随产生大量自由基的细胞群。parkin突变体将成为未来分析细胞和组织退化机制的有价值模型。
