QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, October 11, 2006, 26(41):10514-10523; doi:10.1523/JNEUROSCI.3178-06.2006

This Article Full Text Full Text (PDF) Supplemental data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Shih, A. Y. Articles by Murphy, T. H. Search for Related Content PubMed PubMed Citation Articles by Shih, A. Y. Articles by Murphy, T. H.

 Previous Article  |  Next Article 

Development/Plasticity/Repair
Cystine/Glutamate Exchange Modulates Glutathione Supply for Neuroprotection from Oxidative Stress and Cell Proliferation

Andy Y. Shih,^1,2 Heidi Erb,^1,2 Xiaojian Sun,^1,2 Shigenobu Toda,⁴ Peter W. Kalivas,⁴ and Timothy H. Murphy^1,2,3

¹Kinsmen Laboratory of Neurological Research and Brain Research Center, and Departments of ²Psychiatry and ³Physiology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3, and ⁴Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425

Correspondence should be addressed to Dr. Timothy H. Murphy, 4N1-2255 Wesbrook Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Email: thmurphy{at}interchange.ubc.ca

The cystine/glutamate exchanger (xCT) provides intracellular cyst(e)ine for production of glutathione, a major cellular antioxidant. Using xCT overexpression and underexpression, we present evidence that xCT-dependent glutathione production modulates both neuroprotection from oxidative stress and cell proliferation. In embryonic and adult rat brain, xCT protein was enriched at the CSF–brain barrier (i.e., meninges) and also expressed in the cortex, hippocampus, striatum, and cerebellum. To examine the neuroprotective role of xCT, various non-neuronal cell types (astrocytes, meningeal cells, and peripheral fibroblasts) were cocultured with immature cortical neurons and exposed to oxidative glutamate toxicity, a model involving glutathione depletion. Cultured meningeal cells, which naturally maintain high xCT expression, were more neuroprotective than astrocytes. Selective xCT overexpression in astrocytes was sufficient to enhance glutathione synthesis/release and confer potent glutathione-dependent neuroprotection from oxidative stress. Moreover, normally nonprotective fibroblasts could be re-engineered to be neuroprotective with ectopic xCT overexpression indicating that xCT is a key step in the pathway to glutathione synthesis. Conversely, astrocytes and meningeal cells derived from sut/sut mice (xCT loss-of-function mutants) showed greatly reduced proliferation in culture attributable to increased oxidative stress and thiol deficiency, because growth could be rescued by the thiol-donor -mercaptoethanol. Strikingly, sut/sut mice developed brain atrophy by early adulthood, exhibiting ventricular enlargement, thinning of the cortex, and shrinkage of the striatum. Our results indicate that xCT can provide neuroprotection by enhancing glutathione export from non-neuronal cells such as astrocytes and meningeal cells. Furthermore, xCT is critical for cell proliferation during development in vitro and possibly in vivo.

Key words: xCT; system x; Nrf2; phase 2 detoxification enzymes; oxidative glutamate toxicity; cystine deprivation; meninges; oxidative stress; neuroprotection; neurogenesis

---

Received July 25, 2006; revised Aug. 28, 2006; accepted Aug. 30, 2006.

Correspondence should be addressed to Dr. Timothy H. Murphy, 4N1-2255 Wesbrook Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Email: thmurphy{at}interchange.ubc.ca

This article has been cited by other articles:

				S. K. Garg, R. Banerjee, and J. Kipnis Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype J. Immunol., March 15, 2008; 180(6): 3866 - 3873. [Abstract] [Full Text] [PDF]

				H. Augustin, Y. Grosjean, K. Chen, Q. Sheng, and D. E. Featherstone Nonvesicular Release of Glutamate by Glial xCT Transporters Suppresses Glutamate Receptor Clustering In Vivo J. Neurosci., January 3, 2007; 27(1): 111 - 123. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help