Dysregulation of system xc- expression induced by mutant huntingtin in a striatal neuronal cell line and in R6/2 mice

Natalie M. Frederick, Julie Bertho, Kishan K. Patel, Geraldine T. Petr, Ekaterina Bakradze, Sylvia B. Smith, Paul A. Rosenberg

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Oxidative stress has been implicated in the pathogenesis of Huntington's disease (HD), however, the origin of the oxidative stress is unknown. System xc- plays a role in the import of cystine to synthesize the antioxidant glutathione. We found in the STHdhQ7/Q7 and STHdhQ111/Q111 striatal cell lines, derived from neuronal precursor cells isolated from knock-in mice containing 7 or 111 CAG repeats in the huntingtin gene, that there is a decrease in system xc- function. System xc- is composed of two proteins, the substrate specific transporter, xCT, and an anchoring protein, CD98. The decrease in function in system xc- that we observed is caused by a decrease in xCT mRNA and protein expression in the STHdh Q111/Q111 cells. In addition, we found a decrease in protein and mRNA expression in the transgenic R6/2 HD mouse model at 6 weeks of age. STHdh Q111/Q111 cells have lower basal levels of GSH and higher basal levels of ROS. Acute inhibition of system xc- causes greater increase in oxidative stress in the STHdhQ111/Q111 cells than in the STHdhQ7/Q7 cells. These results suggest that a defect in the regulation of xCT may be involved in the pathogenesis of HD by compromising xCT expression and increasing susceptibility to oxidative stress.

Original languageEnglish (US)
Pages (from-to)59-69
Number of pages11
JournalNeurochemistry International
StatePublished - Oct 2014


  • Glutamate uptake
  • Glutathione
  • Huntington's disease
  • Oxidative stress
  • STHdh cells
  • xCT

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology


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