Neural dysfunction and neurodegeneration in Drosophila Na+/K+ ATPase alpha subunit mutants.
The Na+/K+ ATPase asymmetrically distributes sodium and potassium ions across the plasma membrane to generate and maintain the membrane potential in many cell types. Although these pumps have been hypothesized to be involved in various human neurological disorders, including seizures and neurodegeneration, direct genetic evidence has been lacking. Here, we describe novel mutations in the Drosophila gene encoding the alpha (catalytic) subunit of the Na+/K+ ATPase that lead to behavioral abnormalities, reduced life span, and severe neuronal hyperexcitability. These phenotypes parallel the occurrence of extensive, age-dependent neurodegeneration. We have also discovered that the ATPalpha transcripts undergo alternative splicing that substantially increases the diversity of potential proteins. Our data show that maintenance of neuronal viability is dependent on normal sodium pump activity and establish Drosophila as a useful model for investigating the role of the pump in human neurodegenerative and seizure disorders.
Palladino
Michael J
MJ
Laboratory of Genetics, University of Wisconsin, Madison, Wisconsin 53706, USA. mjpalladino@facstaff.wisc.edu
Bower
Jill E
JE
Kreber
Robert
R
Ganetzky
Barry
B
D000200:Action Potentials; D000483:Alleles; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004330:Drosophila / Q000201:enzymology*; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation; D009410:Nerve Degeneration / Q000209:etiology* / Q000473:pathology; D009422:Nervous System Diseases / Q000209:etiology*; D010243:Paralysis / Q000209:etiology; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D012640:Seizures / Q000209:etiology; D016415:Sequence Alignment; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
D029721:Drosophila Proteins; D021122:Protein Subunits; C472021:ATPalpha protein, Drosophila; D000254:Sodium-Potassium-Exchanging ATPase