Novel mutations affecting the Na, K ATPase alpha model complex neurological diseases and implicate the sodium pump in increased longevity
Novel mutations affecting the Na, K ATPase alpha model complex neurological diseases and implicate the sodium pump in increased longevity
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DOI：
10.1007/s00439-009-0673-2
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发表时间：
2009-09-01
期刊：
影响因子：
5.3
通讯作者：
Palladino, Michael J.
中科院分区：
文献类型：
--
作者：
Ashmore, Lesley J.;Hrizo, Stacy L.;Palladino, Michael J.
影响Na+，K+ATPaseα亚单位的突变至少与两种不同的人类疾病有关，即快速发作的肌张力障碍帕金森综合症(RDP)和家族性偏瘫(FHM)。已有40多个突变被映射到人类ATP1A2和ATP1A3基因，并已知会导致RDP、FHM或FHM的变种，并伴有神经并发症。为了研究Na+，K+ATPase在神经病理学中的作用，我们在果蝇中进行了遗传筛选，以分离影响Na+，K+ATPaseα亚单位的功能丧失的等位基因。这些突变的杂合子果蝇都表现出呼吸减少，这与主要的ATPase功能丧失一致。然而，这些突变并不影响Na+，K+ATPaseα蛋白的所有功能，因为这些突变的纯合子胚胎具有正常的间隔连接、细胞旁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，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进行性应激诱导的运动障碍，提示神经肌肉功能障碍，但神经变性是以等位基因特有的方式观察到的。令人惊讶的是，关于长寿的研究表明，钠泵中轻微的亚型突变显著延长了寿命，这一点得到了Na+，K+ATPase拮抗剂哇巴因的验证。果蝇ATPalpha一系列新的错义等位基因的分离和鉴定为进一步研究这些神经系统疾病以及钠泵功能障碍在动物寿命中的作用提供了基础。
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.