Cystine/glutamate antiporter blockage induces myelin degeneration

Glia. 2016 Aug;64(8):1381-95. doi: 10.1002/glia.23011. Epub 2016 Jun 1.


The cystine/glutamate antiporter is a membrane transport system responsible for the uptake of extracellular cystine and release of intracellular glutamate. It is the major source of cystine in most cells, and a key regulator of extrasynaptic glutamate in the CNS. Because cystine is the limiting factor in the biosynthesis of glutathione, and glutamate is the most abundant neurotransmitter, the cystine/glutamate antiporter is a central player both in antioxidant defense and glutamatergic signaling, two events critical to brain function. However, distribution of cystine/glutamate antiporter in CNS has not been well characterized. Here, we analyzed expression of the catalytic subunit of the cystine/glutamate antiporter, xCT, by immunohistochemistry in histological sections of the forebrain and spinal cord. We detected labeling in neurons, oligodendrocytes, microglia, and oligodendrocyte precursor cells, but not in GFAP(+) astrocytes. In addition, we examined xCT expression and function by qPCR and cystine uptake in primary rat cultures of CNS, detecting higher levels of antiporter expression in neurons and oligodendrocytes. Chronic inhibition of cystine/glutamate antiporter caused high toxicity to cultured oligodendrocytes. In accordance, chronic blockage of cystine/glutamate antiporter as well as glutathione depletion caused myelin disruption in organotypic cerebellar slices. Finally, mice chronically treated with sulfasalazine, a cystine/glutamate antiporter inhibitor, showed a reduction in the levels of myelin and an increase in the myelinated fiber g-ratio. Together, these results reveal that cystine/glutamate antiporter is expressed in oligodendrocytes, where it is a key factor to the maintenance of cell homeostasis. GLIA 2016. GLIA 2016;64:1381-1395.

Keywords: cystine; cystine/glutamate antiporter; glutathione; oligodendrocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / antagonists & inhibitors*
  • Amino Acid Transport System y+ / metabolism
  • Amino Acid Transport Systems, Acidic / antagonists & inhibitors*
  • Amino Acid Transport Systems, Acidic / metabolism
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Cell Death / physiology
  • Cells, Cultured
  • Demyelinating Diseases / metabolism*
  • Demyelinating Diseases / pathology
  • Glutathione / deficiency
  • Mice
  • Microglia / metabolism
  • Microglia / pathology
  • Myelin Sheath / metabolism*
  • Myelin Sheath / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Tissue Culture Techniques


  • Amino Acid Transport System y+
  • Amino Acid Transport Systems, Acidic
  • Slc7a11 protein, mouse
  • xCT protein, rat
  • Glutathione