Dopaminergic neurons of system xc–‐deficient mice are highly protected against 6‐hydroxydopamine‐induced toxicity

Malfunctioning of system xc–, 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 xc˜, to investigate the involvement of this antiporter in PD. Although cystine that is imported via system xc˜ 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 xc˜ 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 xc˜.—Massie, A., Schallier, A., Kim, S. W., Fernando, R., Kobayashi, S., Beck, H., De Bundel, D., Vermoesen, K., Bannai, S., Smolders, I., Conrad, M., Plesnila, N., Sato, H., Michotte, Y. Dopaminergic neurons of system xc "-deficient mice are highly protected against 6-hydroxydopamine-induced toxicity. FASEB J. 25, 1359–1369 (2011). www.fasebj.org