title: α3Na+/K+-ATPase deficiency causes brain ventricle dilation and abrupt embryonic motility in zebrafish.
abstract: Na(+)/K(+)-ATPases are transmembrane ion pumps that maintain ion gradients across the basolateral plasma membrane in all animal cells to facilitate essential biological functions. Mutations in the Na(+)/K(+)-ATPase α3 subunit gene (ATP1A3) cause rapid-onset dystonia-parkinsonism, a rare movement disorder characterized by sudden onset of dystonic spasms and slow movements. In the brain, ATP1A3 is principally expressed in neurons. In zebrafish, the transcripts of the two ATP1A3 orthologs, Atp1a3a and Atp1a3b, show distinct expression in the brain. Surprisingly, targeted knockdown of either Atp1a3a or Atp1a3b leads to brain ventricle dilation, a likely consequence of ion imbalances across the plasma membrane that cause accumulation of cerebrospinal fluid in the ventricle. The brain ventricle dilation is accompanied by a depolarization of spinal Rohon-Beard neurons in Atp1a3a knockdown embryos, suggesting impaired neuronal excitability. This is further supported by Atp1a3a or Atp1a3b knockdown results where altered responses to tactile stimuli as well as abnormal motility were observed. Finally, proteomic analysis identified several protein candidates highlighting proteome changes associated with the knockdown of Atp1a3a or Atp1a3b. Our data thus strongly support the role of α3Na(+)/K(+)-ATPase in zebrafish motility and brain development, associating for the first time the α3Na(+)/K(+)-ATPase deficiency with brain ventricle dilation.
authors: Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, DK-1057 Copenhagen, Denmark.
authors: Canan
authors: C
authors: Doğanli
authors: Hans C
authors: HC
authors: Beck
authors: Angeles B
authors: AB
authors: Ribera
authors: Claus
authors: C
authors: Oxvig
authors: Karin
authors: K
authors: Lykke-Hartmann
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000196:embryology* / Q000502:physiology; D002490:Central Nervous System / Q000196:embryology / Q000378:metabolism; D002552:Cerebral Ventricles / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D017403:In Situ Hybridization; D008564:Membrane Potentials; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D040901:Proteomics / Q000379:methods; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000502:physiology*
chemical_list: C581316:ATP1A3 protein, zebrafish; D029961:Zebrafish Proteins; D049452:Green Fluorescent Proteins; D000254:Sodium-Potassium-Exchanging ATPase
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