Neural Dysfunction and Neurodegeneration inDrosophilaNa+/K+ATPase Alpha Subunit Mutants

Palladino, Michael J.; Bower, Jill E.; Kreber, Robert; Ganetzky, Barry

doi:10.1523/jneurosci.23-04-01276.2003

Cited by 113 publications

(157 citation statements)

References 56 publications

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“…In the central nervous system, mutations in Na,K-ATPase are known to cause neuronal dysfunction and neurodegeneration in Drosophila (8), familial hemiplegic migraine in humans (9), and rapidonset dystonia-Parkinsonism (10). In addition to maintaining the electrochemical gradient, the Na,K-ATPase has been shown to act as a receptor and signal transducer.…”

mentioning

confidence: 99%

Na,K-ATPase signal transduction triggers CREB activation and dendritic growth

Desfrère¹,

Karlsson²,

Hiyoshi³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic growth is pivotal in the neurogenesis of cortical neurons. The sodium pump, or Na,K-ATPase, is an evolutionarily conserved protein that, in addition to its central role in establishing the electrochemical gradient, has recently been reported to function as a receptor and signaling mediator. Although a large body of evidence points toward a dual function for the Na,K-ATPase, few biological implications of this signaling pathway have been described. Here we report that Na,K-ATPase signal transduction triggers dendritic growth as well as a transcriptional program dependent on cAMP response element binding protein (CREB) and cAMP response element (CRE)-mediated gene expression, primarily regulated via Ca 2+ /calmodulin-dependent protein (CaM) kinases. The signaling cascade mediating dendritic arbor growth also involves intracellular Ca 2+ oscillations and sustained phosphorylation of mitogen-activated protein (MAP) kinases. Thus, our results suggest a novel role for the Na,K-ATPase as a modulator of dendritic growth in developing neurons.

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mentioning

confidence: 99%

Na,K-ATPase signal transduction triggers CREB activation and dendritic growth

Desfrère¹,

Karlsson²,

Hiyoshi³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Numerous studies in which half-site phosphorylation and halfor quarter-site ATP-analog binding stoichiometries have been interpreted in a model that proposes that the Na,K-ATPase co-exits simultaneously in the E1ATP, E2ATP, or EPATP forms (42). The existence of such oligomerization of the Na,KATPase in native membranes provides a mechanism that can explain the recent observation of dominant-negative ␣-mutants in Drosophila (43).…”

Section: Resultsmentioning

confidence: 99%

Oligomerization of the Na,K-ATPase in Cell Membranes

Laughery

Todd

Kaplan

2004

Journal of Biological Chemistry

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The higher order oligomeric state of the Na,K-ATPase ␣␤ heterodimer in cell membranes is the subject of controversy. We have utilized the baculovirus-infected insect cell system to express Na,K-ATPase with ␣-subunits bearing either His 6 or FLAG epitopes at the carboxyl terminus. Each of these constructs produced functional Na,K-ATPase ␣␤ heterodimers that were delivered to the plasma membrane (PM). Cells were simultaneously co-infected with viruses encoding ␣-His/␤ and ␣-FLAG/␤ Na,K-ATPases. Co-immunoprecipitation of the Histagged ␣-subunit in the endoplasmic reticulum (ER) and PM fractions of co-infected cells by the anti-FLAG antibody demonstrates that protein-protein associations exist between these heterodimers. This suggests the Na,KATPase is present in cell membranes in an oligomeric state of at least (␣␤) 2 composition. Deletion of 256 amino acid residues from the central cytoplasmic loop of the ␣-subunit results in the deletion ␣-4,5-loop-less (␣-4,5LL), which associates with ␤ but is confined to the ER. Co-immunoprecipitation demonstrates that when this inactive ␣-4,5LL/␤ heterodimer is co-expressed with wild-type ␣␤, oligomers of wild-type ␣␤ and ␣-4,5LL/␤ form in the ER, but the ␣-4,5LL mutant remains retained in the ER, and the wild-type protein is still delivered to the PM. We conclude that the Na,K-ATPase is present as oligomers of the monomeric ␣␤ heterodimer in native cell membranes.

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“…Life span and behavioral analysis: Life span analysis was performed as previously described (Palladino et al 2003). Stress sensitivity (a.k.a.…”

Section: Methodsmentioning

confidence: 99%

Degradation of Functional Triose Phosphate Isomerase Protein UnderliessugarkillPathology

Seigle

Celotto²,

Palladino

2008

Genetics

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Triose phosphate isomerase (TPI) deficiency glycolytic enzymopathy is a progressive neurodegenerative condition that remains poorly understood. The disease is caused exclusively by specific missense mutations affecting the TPI protein and clinically features hemolytic anemia, adult-onset neurological impairment, degeneration, and reduced longevity. TPI has a well-characterized role in glycolysis, catalyzing the isomerization of dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (G3P); however, little is known mechanistically about the pathogenesis associated with specific recessive mutations that cause progressive neurodegeneration. Here, we describe key aspects of TPI pathogenesis identified using the TPI sugarkill mutation, a Drosophila model of human TPI deficiency. Specifically, we demonstrate that the mutant protein is expressed, capable of forming a homodimer, and is functional. However, the mutant protein is degraded by the 20S proteasome core leading to loss-of-function pathogenesis.

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Neural Dysfunction and Neurodegeneration inDrosophilaNa⁺/K⁺ATPase Alpha Subunit Mutants

Cited by 113 publications

References 56 publications

Na,K-ATPase signal transduction triggers CREB activation and dendritic growth

Na,K-ATPase signal transduction triggers CREB activation and dendritic growth

Oligomerization of the Na,K-ATPase in Cell Membranes

Degradation of Functional Triose Phosphate Isomerase Protein UnderliessugarkillPathology

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