Cystine/glutamate antiporter blockage induces myelin degeneration
Glia. 2016-06-01; 64(8): 1381-1395
DOI: 10.1002/glia.23011
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1. Glia. 2016 Aug;64(8):1381-95. doi: 10.1002/glia.23011. Epub 2016 Jun 1.
Cystine/glutamate antiporter blockage induces myelin degeneration.
Soria FN(1), Zabala A(1), Pampliega O(1), Palomino A(1), Miguelez C(2), Ugedo
L(2), Sato H(3), Matute C(1), Domercq M(1).
Author information:
(1)Achucarro Basque Center for Neurosciences, CIBERNED and Departamento de
Neurociencias, Universidad Del País Vasco, Leioa, Spain.
(2)Departamento de Farmacología, Universidad Del País Vasco, Leioa, Spain.
(3)Department of Food and Applied Life Sciences, Faculty of Agriculture, Yamagata
University, Tsuruoka, Japan.
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.
© 2016 Wiley Periodicals, Inc.
DOI: 10.1002/glia.23011
PMID: 27247047 [Indexed for MEDLINE]