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 STHdhQ111/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. STHdhQ111/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.

Transcriptional control of amino acid homeostasis is disrupted in Huntington’s disease

“…As HD is characterized by aberrant cysteine metabolism, with CSE as well as cysteine transporters altered alongside abnormalities in amino acid levels (8,23,24), we explored the regulation of ATF4 and its targets in a striatal cell culture model of HD harboring the expanded glutamine repeats characteristic of mHtt (25). In HD, basal CSE expression is diminished due to sequestration of SP1, the basal transcriptional activator for CSE, by mHtt (8) (Fig.…”

“…The perturbation stems from the oxidative stress generated by cysteine deficits associated with the disease. In addition to depletion of CSE, the biosynthetic enzyme for cysteine, levels of two cysteine/cystine transporters, the excitatory amino acid transporter 3 (EAAT3/EAAC1), and the solute carrier family 7, member 11 (SLC7A11/xCT), are also diminished in HD (23,24). ATF4 regulates transcription of SLC7A11/xCT as well as CSE.…”

Astrocyte truncated tropomyosin receptor kinase B mediates brain‐derived neurotrophic factor anti‐apoptotic effect leading to neuroprotection

“…Decreased xCT expression was shown in the striatum of HD mice and in neurons expressing mHtt (Frederick et al . ). BDNF increases xCT levels that were reduced by 3‐NP treatment as a new mechanism of BDNF antioxidant action.…”

The importance of the excitatory amino acid transporter 3 (EAAT3)

“…It should therefore be noted that these studies are not directly comparable. In a murine cellular model of Huntington’s disease, plasma membrane EAAT3 was found to be upregulated (Petr et al, 2013), with a concomitant decrease in X c - expression later described by the same group (Frederick et al, 2014). This is consistent with an EAAT3 up-regulation in the neuronal Huntington’s cell line being a compensatory mechanism for maintaining Cys uptake during the observed X c - decrease, and a functional role of both transport systems.…”