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α3Na+/K+-ATPase deficiency causes brain ventricle dilation and abrupt embryonic motility in zebrafish

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  • Canan Doganli, Denmark
  • Hans Christian Beck, Department of Clinical Biochemistry and Pharmacology, Centre for Clinical Proteomics, Odense University Hospital, Denmark
  • Angeles B Ribera, Department of Physiology and Biophysics, University of Colorado Denver, United States
  • Claus Oxvig
  • Karin Lykke-Hartmann
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.
Original languageEnglish
JournalJournal of Biological Chemistry
Pages (from-to)8862-8874
Number of pages12
Publication statusPublished - 29 Mar 2013

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