Prion protein facilitates uptake of zinc into neuronal cells

Nicole T. Watt, David R. Taylor, Talitha L. Kerrigan, Heledd H. Griffiths, Jo V. Rushworth, Isobel J. Whitehouse and Nigel M. Hooper ()
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Nicole T. Watt: Faculty of Biological Sciences, School of Molecular and Cellular Biology, University of Leeds
David R. Taylor: Faculty of Biological Sciences, School of Molecular and Cellular Biology, University of Leeds
Talitha L. Kerrigan: Leeds Institute of Genetics, Health and Therapeutics, University of Leeds
Heledd H. Griffiths: Faculty of Biological Sciences, School of Molecular and Cellular Biology, University of Leeds
Jo V. Rushworth: Faculty of Biological Sciences, School of Molecular and Cellular Biology, University of Leeds
Isobel J. Whitehouse: Faculty of Biological Sciences, School of Molecular and Cellular Biology, University of Leeds
Nigel M. Hooper: Faculty of Biological Sciences, School of Molecular and Cellular Biology, University of Leeds

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: Abstract Zinc is released into the synaptic cleft upon exocytotic stimuli, although the mechanism for its reuptake into neurons is unresolved. Here we show that the cellular prion protein enhances the uptake of zinc into neuronal cells. This prion-protein-mediated zinc influx requires the octapeptide repeats and amino-terminal polybasic region in the prion protein, but not its endocytosis. Selective antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors block the prion protein-mediated zinc uptake, and the prion protein co-immunoprecipitates with both GluA1 and GluA2 AMPA receptor subunits. Zinc-sensitive intracellular tyrosine phosphatase activity is decreased in cells expressing prion protein and increased in the brains of prion-protein-null mice, providing evidence of a physiological consequence of this process. Prion protein-mediated zinc uptake is ablated in cells expressing familial associated mutants of the protein and in prion-infected cells. These data suggest that alterations in the cellular prion protein-mediated zinc uptake may contribute to neurodegeneration in prion and other neurodegenerative diseases.

Date: 2012
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DOI: 10.1038/ncomms2135

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