Journal
GLIA
Volume 64, Issue 8, Pages 1381-1395Publisher
WILEY
DOI: 10.1002/glia.23011
Keywords
cystine/glutamate antiporter; oligodendrocytes; cystine; glutathione
Categories
Funding
- Spanish Ministry of Education and Science [SAF2013-45084-R]
- FEDER Funds
- Fundacion Koplowitz
- Basque Government
- University of the Basque Country (UPV/EHU)
- Centro de Investigacion Biomedica en Red, Enfermedades Neurodegenerativas (CIBERNED)
- Instituto de Salud Carlos III Fellowship
- University of the Basque Country Fellowship
- Spanish Ministry of Education and Science Fellowship
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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.
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