Prion protein facilitates uptake of zinc into neuronal cells.
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.
Faculty of Biological Sciences, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
Nicole T
NT
Watt
David R
DR
Taylor
Talitha L
TL
Kerrigan
Heledd H
HH
Griffiths
Jo V
JV
Rushworth
Isobel J
IJ
Whitehouse
Nigel M
NM
Hooper
D000818:Animals; D045744:Cell Line, Tumor; D004705:Endocytosis; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology; D000072002:Prion Proteins; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D014162:Transfection; D015032:Zinc / Q000378:metabolism*
D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; D000072002:Prion Proteins; D011328:Prions; C122036:Prnd protein, mouse; C512657:Prnp protein, mouse; D021122:Protein Subunits; D018091:Receptors, AMPA; C523856:Sprn protein, mouse; D017027:Protein Tyrosine Phosphatases; D015032:Zinc