title: Cystine/glutamate antiporter blockage induces myelin degeneration.
abstract: 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.
authors.affiliation: Achucarro Basque Center for Neurosciences, CIBERNED and Departamento de Neurociencias, Universidad Del País Vasco, Leioa, Spain.
authors.forename: Federico N
authors.initials: FN
authors.lastname: Soria
authors.affiliation: Achucarro Basque Center for Neurosciences, CIBERNED and Departamento de Neurociencias, Universidad Del País Vasco, Leioa, Spain.
authors.forename: Alazne
authors.initials: A
authors.lastname: Zabala
authors.affiliation: Achucarro Basque Center for Neurosciences, CIBERNED and Departamento de Neurociencias, Universidad Del País Vasco, Leioa, Spain.
authors.forename: Olatz
authors.initials: O
authors.lastname: Pampliega
authors.affiliation: Achucarro Basque Center for Neurosciences, CIBERNED and Departamento de Neurociencias, Universidad Del País Vasco, Leioa, Spain.
authors.forename: Aitor
authors.initials: A
authors.lastname: Palomino
authors.affiliation: Departamento de Farmacología, Universidad Del País Vasco, Leioa, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Miguelez
authors.affiliation: Departamento de Farmacología, Universidad Del País Vasco, Leioa, Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ugedo
authors.affiliation: Department of Food and Applied Life Sciences, Faculty of Agriculture, Yamagata University, Tsuruoka, Japan.
authors.forename: Hideyo
authors.initials: H
authors.lastname: Sato
authors.affiliation: Achucarro Basque Center for Neurosciences, CIBERNED and Departamento de Neurociencias, Universidad Del País Vasco, Leioa, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
authors.affiliation: Achucarro Basque Center for Neurosciences, CIBERNED and Departamento de Neurociencias, Universidad Del País Vasco, Leioa, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Domercq
mesh_terms: D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors* / Q000378:metabolism; D026922:Amino Acid Transport Systems, Acidic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology; D005978:Glutathione / Q000172:deficiency; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D046509:Tissue Culture Techniques
chemical_list: D027182:Amino Acid Transport System y+; D026922:Amino Acid Transport Systems, Acidic; D005978:Glutathione; C492255:Slc7a11 protein, mouse; C000723960:Slc7a11 protein, rat
keywords: cystine; cystine/glutamate antiporter; glutathione; oligodendrocytes