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

Oxidative stress has been implicated in the pathogenesis of Huntington's disease (HD), however, the origin of the oxidative stress is unknown. System x_c^- plays a role in the import of cystine to synthesize the antioxidant glutathione. We found in the STHdh^Q7/Q7 and STHdh^Q111/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 x_c^- function. System x_c^- is composed of two proteins, the substrate specific transporter, xCT, and an anchoring protein, CD98. The decrease in function in system x_c^- 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 x_c^- causes greater increase in oxidative stress in the STHdh^Q111/Q111 cells than in the STHdh^Q7/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.