title: Dysregulation of system xc(-) expression induced by mutant huntingtin in a striatal neuronal cell line and in R6/2 mice.
abstract: 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 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 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 6weeks 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 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.
authors.affiliation: Department of Neurology and F.M. Kirby Neurobiology Center, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Frederick
authors.affiliation: Department of Neurology and F.M. Kirby Neurobiology Center, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA; Department of Genetics, Université Paris-Diderot, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Bertho
authors.affiliation: Department of Neurology and F.M. Kirby Neurobiology Center, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kishan K
authors.initials: KK
authors.lastname: Patel
authors.affiliation: Department of Neurology and F.M. Kirby Neurobiology Center, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Geraldine T
authors.initials: GT
authors.lastname: Petr
authors.affiliation: Department of Neurology and F.M. Kirby Neurobiology Center, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA; David Tvildiani Medical University, Tbilisi, Georgia.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Bakradze
authors.affiliation: Department of Cellular Biology and Anatomy and Department of Ophthalmology, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Sylvia B
authors.initials: SB
authors.lastname: Smith
authors.affiliation: Department of Neurology and F.M. Kirby Neurobiology Center, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. Electronic address: paul.rosenberg@childrens.harvard.edu.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rosenberg
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D017931:DNA Primers; D000071058:Huntingtin Protein; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D018911:Trinucleotide Repeats
chemical_list: D027182:Amino Acid Transport System y+; D017931:DNA Primers; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C492255:Slc7a11 protein, mouse
keywords: Glutamate uptake; Glutathione; Huntington’s disease; Oxidative stress; STHdh cells; xCT