Ashmore Lesley J, Hrizo Stacy L, Paul Sarah M, Van Voorhies Wayne A, Beitel Greg J, Palladino Michael J
Department of Pharmacology & Chemical Biology, Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, 3501 Fifth Ave., BST3 7042, Pittsburgh, PA 15260, USA.
Hum Genet. 2009 Sep;126(3):431-47. doi: 10.1007/s00439-009-0673-2. Epub 2009 May 12.
Mutations affecting the Na(+), K(+) ATPase alpha subunit have been implicated in at least two distinct human diseases, rapid-onset dystonia Parkinsonism (RDP), and familial hemiplegic migraine (FHM). Over 40 mutations have been mapped to the human ATP1A2 and ATP1A3 genes and are known to result in RDP, FHM or a variant of FHM with neurological complications. To develop a genetically tractable model system for investigating the role of the Na(+), K(+) ATPase in neural pathologies we performed genetic screens in Drosophila melanogaster to isolate loss-of-function alleles affecting the Na(+), K(+) ATPase alpha subunit. Flies heterozygous for these mutations all exhibit reduced respiration, consistent with a loss-of-function in the major ATPase. However, these mutations do not affect all functions of the Na(+), K(+) ATPase alpha protein since embryos homozygous for these mutations have normal septate junction paracellular barrier function and tracheal morphology. Importantly, all of these mutations cause neurological phenotypes and, akin to the mutations that cause RDP and FHM, these new alleles are missense mutations. All of these alleles exhibit progressive stress-induced locomotor impairment suggesting neuromuscular dysfunction, yet neurodegeneration is observed in an allele-specific manner. Surprisingly, studies of longevity demonstrate that mild hypomorphic mutations in the sodium pump significantly improve longevity, which was verified using the Na(+), K(+) ATPase antagonist ouabain. The isolation and characterization of a series of new missense alleles of ATPalpha in Drosophila provides the foundation for further studies of these neurological diseases and the role of sodium pump impairment in animal longevity.
影响钠钾ATP酶α亚基的突变与至少两种不同的人类疾病有关，即快速发作性肌张力障碍帕金森综合征（RDP）和家族性偏瘫性偏头痛（FHM）。已在人类ATP1A2和ATP1A3基因中定位了40多种突变，已知这些突变会导致RDP、FHM或伴有神经并发症的FHM变体。为了开发一个用于研究钠钾ATP酶在神经病理学中作用的遗传易处理模型系统，我们在黑腹果蝇中进行了遗传筛选，以分离影响钠钾ATP酶α亚基的功能缺失等位基因。这些突变的杂合子果蝇均表现出呼吸作用降低，这与主要ATP酶的功能丧失一致。然而，这些突变并不影响钠钾ATP酶α蛋白的所有功能，因为这些突变的纯合子胚胎具有正常的紧密连接旁细胞屏障功能和气管形态。重要的是，所有这些突变都会导致神经表型，并且与导致RDP和FHM的突变类似，这些新的等位基因都是错义突变。所有这些等位基因都表现出渐进性应激诱导的运动功能障碍，提示神经肌肉功能障碍，但神经退行性变是以等位基因特异性方式观察到的。令人惊讶的是，寿命研究表明，钠泵中的轻度亚效突变可显著延长寿命，这一点已通过钠钾ATP酶拮抗剂哇巴因得到验证。果蝇中一系列新的ATPα错义等位基因的分离和表征为进一步研究这些神经疾病以及钠泵损伤在动物寿命中的作用奠定了基础。
