Induction of cellular prion protein gene expression by copper in neurons

Lorena Varela-Nallar, Enrique M. Toledo, Luis F. Larrondo, Ana L B Cabral, Vilma R. Martins, Nibaldo C. Inestrosa

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

Abstract

Prion diseases are caused by the conformational transition of the native α-helical cellular prion protein (PrPC) into a β-sheet pathogenic isoform. However, the normal physiological function of PrP C remains elusive. We report herein that copper induces PrP C expression in primary hippocampal and cortical neurons. PrP C induced by copper has a normal glycosylation pattern, is proteinase K-sensitive and reaches the cell surface attached by a glycosyl phosphatidylinositol anchor. Immunofluorescence analysis revealed that copper induces PrPC levels in the cell surface and in an intracellular compartment that we identified as the Golgi complex. In addition, copper induced the activity of a reporter vector driven by the rat PrPC gene (Prnp) promoter stably transfected into PC12 cells, whereas no effect was observed in glial C6 clones. Also cadmium, but not zinc or manganese, upregulated Prnp promoter activity in PC12 clones. Progressive deletions of the promoter revealed that the region essential for copper modulation contains a putative metal responsive element. Although electrophoretic mobility shift assay demonstrated nuclear protein binding to this element, supershift analysis showed that this is not a binding site for the metal responsive transcription factor-1 (MTF-1). The MTF-1-independent transcriptional activation of Prnp is supported by the lack of Prnp promoter activation by zinc. These findings demonstrate that Prnp expression is upregulated by copper in neuronal cells by an MTF-1-independent mechanism, and suggest a metalspecific modulation of Prnp in neurons.

Original languageEnglish
Pages (from-to)C271-C281
JournalAmerican Journal of Physiology - Cell Physiology
Volume290
Issue number1
DOIs
Publication statusPublished - Jan 2006

Keywords

  • Metal responsive element
  • Metal responsive transcription factor-1
  • Neuronal cells
  • Phosphatidylinositol-specific phospholipase
  • Prnp

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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