Novel mutations affecting the Na, K ATPase alpha model complex neurological diseases and implicate the sodium pump in increased longevity

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-009-0673-2) contains supplementary material, which is available to authorized users.

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

“…Simple organisms such as Drosophila melanogaster provide an easily-accessible and genetically tractable system for the modelling of genetic diseases and random mutagenesis of the fly equivalent of the human ATP1A3 was used to induce an RDP phenotype in Drosophila [32]. All mutations resulted in a loss of function of the ATPase which could be phenocopied by the selective inhibition of the α3-ATPase protein by ouabain and some degree of stress-inducible motor impairment.…”

Ecdysone regulates morphogenesis and function of malpighian tubules in Drosophila melanogaster through EcR-B2 isoform

“…Further we wanted to know whether disruption of (Na þ /K þ )-ATPase directly affects Na þ ion concentration in MTs, we checked Na þ ion levels in (Na þ /K þ )-ATPase mutants (Palladino et al, 2003;Ashmore et al, 2009). Intensity of Na þ was significantly reduced in mutants compared to wild type (Fig.…”

Invertebrate Models of Dystonia

“…The beta subunit is hypothesized to regulate processes such as the transport to, and insertion into, the membrane [105]. The loss of proper function of specific alpha subunits of Na + /K + ATPase can result in two different human neurological diseases, familial hemiplegic migraine and DYT12 dystonia [106]. While the mechanism underlying these disorders remains undefined, studies in C. elegans and Drosophila have begun to provide clues to Na The C. elegans Na + / K + ATPase α subunit, EAT-6 ( Table 1), was originally identified in a genetic screen for pharyngeal pumping (feeding) defects [107].…”

“…Following mechanical stress, recovery is immediate in wild type controls, but ATPalpha mutants experience a delay, whereby temporarily paralysis is observed. This locomotory defect is progressive, with older animals displaying more paralysis [106]. While some Drosophila ATPalpha mutants show this phenotype following mechanical stress, others display temperaturedependent paralysis and reduced longevity [111].…”

“…While some Drosophila ATPalpha mutants show this phenotype following mechanical stress, others display temperaturedependent paralysis and reduced longevity [111]. A subset of ATPalpha missense mutants also exhibit vacuolar neuromuscular pathology changes throughout the brain [106,111]. Two additional ATPalpha dominant temperaturesensitive (TS) paralytic mutations result in severe neurodegeneration.…”