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 as well as excitotoxicity, both important phenomenons in the pathogenesis of Parkinson's disease. We used mice lacking xCT (xCT-/- mice), the specific subunit of system xc-, to investigate the involvement of this antiporter in Parkinson's disease. 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 the expectations, xCT-/- mice were less susceptible to 6-hydroxydopamine (6-OHDA)-induced neurodegeneration in the substantia nigra pars compacta compared to their age-matched wildtype littermates. This reduced sensitivity to a Parkinson's disease inducing toxin, might be related to the significantly reduced (70%) striatal extracellular glutamate levels that were observed in mice lacking xCT. The current data point towards system xc- as a possible target for the development of new pharmacotherapies for the treatment of Parkinson's disease and emphasizes the need to continue the search for specific ligands for system xc-.