Altered manganese homeostasis and manganese toxicity in a huntington's disease striatal cell model are not explained by defects in the iron transport system

B. Blairanne Williams, Gunnar F. Kwakye, Michal Wegrzynowicz, Daphne Li, Michael Aschner, Keith M. Erikson, Aaron B. Bowman

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Expansion of a polyglutamine tract in Huntingtin (Htt) leads to the degeneration of medium spiny neurons in Huntington's disease (HD). Furthermore, the HTT gene has been functionally linked to iron (Fe) metabolism, and HD patients show alterations in brain and peripheral Fe homeostasis. Recently, we discovered that expression of mutant HTT is associated with impaired manganese (Mn) uptake following overexposure in a striatal neuronal cell line and mouse model of HD. Here we test the hypothesis that the transferrin receptor (TfR)-mediated Fe uptake pathway is responsible for the HD-associated defects in Mn uptake. Western blot analysis showed that TfR levels are reduced in the mutant STHdhQ111/Q111 striatal cell line, whereas levels of the Fe and Mn transporter, divalent metal transporter 1 (DMT1), are unchanged. To stress the Fe transport system, we exposed mutant and wild-type cells to elevated Fe(III), which revealed a subtle impairment in net Fe uptake only at the highest Fe exposures. In contrast, the HD mutant line exhibited substantial deficits in net Mn uptake, even under basal conditions. Finally, to functionally evaluate a role for Fe transporters in the Mn uptake deficit, we examined Mn toxicity in the presence of saturating Fe(III) levels. Although Fe(III) exposure decreased Mn neurotoxicity, it did so equally for wild-type and mutant cells. Therefore, although Fe transporters contribute to Mn uptake and toxicity in the striatal cell lines, functional alterations in this pathway are insufficient to explain the strong Mn resistance phenotype of this HD cell model.

Original languageEnglish (US)
Pages (from-to)169-179
Number of pages11
JournalToxicological Sciences
Volume117
Issue number1
DOIs
StatePublished - Jun 13 2010
Externally publishedYes

Keywords

  • Huntington's disease
  • Iron
  • Manganese
  • Neurotoxicity
  • Transferrin receptor

ASJC Scopus subject areas

  • Toxicology

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