Dopaminergic neurons of system x(c)⁻-deficient mice are highly protected against 6-hydroxydopamine-induced toxicity.

Abstract

Malfunctioning of system x(c)(-), responsible for exchanging intracellular glutamate for extracellular cystine, can cause oxidative stress and excitotoxicity, both important phenomena in the pathogenesis of Parkinson's disease (PD). We used mice lacking xCT (xCT(-/-) mice), the specific subunit of system x(c)(-), to investigate the involvement of this antiporter in PD. Although cystine that is imported via system x(c)(-) is reduced to cysteine, the rate-limiting substrate in the synthesis of glutathione, deletion of xCT did not result in decreased glutathione levels in striatum. Accordingly, no signs of increased oxidative stress could be observed in striatum or substantia nigra of xCT(-/-) mice. In sharp contrast to expectations, xCT(-/-) mice were less susceptible to 6-hydroxydopamine (6-OHDA)-induced neurodegeneration in the substantia nigra pars compacta compared to their age-matched wild-type littermates. This reduced sensitivity to a PD-inducing toxin might be related to the decrease of 70% in striatal extracellular glutamate levels that was observed in mice lacking xCT. The current data point toward system x(c)(-) as a possible target for the development of new pharmacotherapies for the treatment of PD and emphasize the need to continue the search for specific ligands for system x(c)(-).

• Authors: Ann Massie, Anneleen Schallier, Seong Woong Kim, Ruani Fernando, Sho Kobayashi, Heike Beck, Dimitri De Bundel, Katia Vermoesen, Shiro Bannai, Ilse Smolders, Marcus Conrad, Nikolaus Plesnila, Hideyo Sato, Yvette Michotte
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 25 Issue 4 Pg. 1359-69 (Apr 2011) ISSN: 1530-6860 [Electronic] United States
• PMID: 21191088 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Transport System y+
• Slc7a11 protein, mouse
• Glutamic Acid
• Cystine
• Oxidopamine
• Glutathione
• Dopamine

Topics

• Aging (physiology)
• Amino Acid Transport System y+ (deficiency, physiology)
• Animals
• Corpus Striatum (metabolism)
• Cystine (metabolism)
• Dopamine (physiology)
• Glioma (metabolism)
• Glutamic Acid (metabolism)
• Glutathione (metabolism)
• Mice
• Mice, Knockout
• Neurodegenerative Diseases (prevention & control)
• Neurons (drug effects, metabolism)
• Oxidopamine (toxicity)
• Substantia Nigra (metabolism)
• Tumor Cells, Cultured