An iron-responsive element type II in the 5′-untranslated region of the Alzheimer's amyloid precursor protein transcript

Jack T. Rogers, Jeffrey D. Randall, Catherine M. Cahill, Paul S. Eder, Xudong Huang, Hiromi Gunshin, Lorene Leiter, Jay McPhee, Satinder S. Sarang, Tada Utsuki, Nigel H. Greig, Debomoy K. Lahiri, Rudolph E. Tanzi, Ashley I. Bush, Tony Giordano, Steve R. Gullans

Research output: Contribution to journalArticle

407 Scopus citations

Abstract

Iron-responsive elements (IREs) are the RNA stem loops that control cellular iron homeostasis by regulating ferritin translation and transferrin receptor mRNA stability. We mapped a novel iron-responsive element (IRE-Type II) within the 5′-untranslated region (5′-UTR) of the Alzheimer's amyloid precursor protein (APP) transcript (+51 to +94 from the 5′-cap site). The APP mRNA IRE is located immediately upstream of an interleukin-1 responsive acute box domain (+101 to +146). APP 5′-UTR conferred translation was selectively down-regulated in response to intracellular iron chelation using three separate reporter assays (chloramphenicol acetyltransferase, luciferase, and red fluorescent protein reflecting an inhibition of APP holoprotein translation in response to iron chelation. Iron influx reversed this inhibition. As an internal control to ensure specificity, a viral internal ribosome entry sequence was unresponsive to intracellular iron chelation with desferrioxamine. Using RNA mobility shift assays, the APP 5′-UTRs, encompassing the IRE, bind specifically to recombinant iron-regulatory proteins (IRP) and to IRP from neuroblastoma cell lysates. IRP binding to the APP 5′-UTR is reduced after treatment of cells with desferrioxamine and increased after interleukin-1 stimulation. IRP binding is abrogated when APP cRNA probe is mutated in the core IRE domain (A4 bases:A83AGAG86). Iron regulation of APP mRNA through the APP 5′-UTR points to a role for iron in the metabolism of APP and confirms that this RNA structure can be a target for the selection of small molecule drugs, such as desferrioxamine (Fe chelator) and clioquinol (Fe, Cu, and Zn chelator), which reduce Aβ peptide burden during Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)45518-45528
Number of pages11
JournalJournal of Biological Chemistry
Volume277
Issue number47
DOIs
StatePublished - Nov 22 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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