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 journalArticle

15 Citations (Scopus)

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 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
Volume76
DOIs
StatePublished - Jan 1 2014

Fingerprint

Corpus Striatum
Huntington Disease
Oxidative Stress
Cell Line
Proteins
Messenger RNA
Cystine
Glutathione
Antioxidants
Genes

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

Dysregulation of system xc- expression induced by mutant huntingtin in a striatal neuronal cell line and in R6/2 mice. / Frederick, Natalie M.; Bertho, Julie; Patel, Kishan K.; Petr, Geraldine T.; Bakradze, Ekaterina; Smith, Sylvia B; Rosenberg, Paul A.

In: Neurochemistry International, Vol. 76, 01.01.2014, p. 59-69.

Research output: Contribution to journalArticle

Frederick, Natalie M. ; Bertho, Julie ; Patel, Kishan K. ; Petr, Geraldine T. ; Bakradze, Ekaterina ; Smith, Sylvia B ; Rosenberg, Paul A. / Dysregulation of system xc- expression induced by mutant huntingtin in a striatal neuronal cell line and in R6/2 mice. In: Neurochemistry International. 2014 ; Vol. 76. pp. 59-69.
@article{75bb3bb696d345869352fe8f89974d32,
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 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.",
keywords = "Glutamate uptake, Glutathione, Huntington's disease, Oxidative stress, STHdh cells, xCT",
author = "Frederick, {Natalie M.} and Julie Bertho and Patel, {Kishan K.} and Petr, {Geraldine T.} and Ekaterina Bakradze and Smith, {Sylvia B} and Rosenberg, {Paul A.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1016/j.neuint.2014.06.017",
language = "English (US)",
volume = "76",
pages = "59--69",
journal = "Neurochemistry International",
issn = "0197-0186",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Dysregulation of system xc- expression induced by mutant huntingtin in a striatal neuronal cell line and in R6/2 mice

AU - Frederick, Natalie M.

AU - Bertho, Julie

AU - Patel, Kishan K.

AU - Petr, Geraldine T.

AU - Bakradze, Ekaterina

AU - Smith, Sylvia B

AU - Rosenberg, Paul A.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - Glutamate uptake

KW - Glutathione

KW - Huntington's disease

KW - Oxidative stress

KW - STHdh cells

KW - xCT

UR - http://www.scopus.com/inward/record.url?scp=84905165974&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905165974&partnerID=8YFLogxK

U2 - 10.1016/j.neuint.2014.06.017

DO - 10.1016/j.neuint.2014.06.017

M3 - Article

VL - 76

SP - 59

EP - 69

JO - Neurochemistry International

JF - Neurochemistry International

SN - 0197-0186

ER -