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The astrocytic cystine/glutamate antiporter system x  c   –  (with xCT as the specific subunit) imports cystine in exchange for glutamate and has been shown to interact with multiple pathways in the brain that are dysregulated in age-related neurological disorders, including glutamate homeostasis, redox balance, and neuroinflammation. In the current study, we investigated the effect of genetic xCT deletion on lactacystin (LAC)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of the nigrostriatal pathway, as models for Parkinson’s disease (PD). Dopaminergic neurons of adult xCT knock-out mice (xCT –/– ) demonstrated an equal susceptibility to intranigral injection of the proteasome inhibitor LAC, as their wild-type (xCT +/+ ) littermates. Contrary to adult mice, aged xCT –/–  mice showed a significant decrease in LAC-induced degeneration of nigral dopaminergic neurons, depletion of striatal dopamine (DA) and neuroinflammatory reaction, compared to age-matched xCT +/+  littermates. Given this age-related protection, we further investigated the sensitivity of aged xCT –/–  mice to chronic and progressive MPTP treatment. However, in accordance with our previous observations in adult mice ( Bentea et al., 2015a ), xCT deletion did not confer protection against MPTP-induced nigrostriatal degeneration in aged mice. We observed an increased loss of nigral dopaminergic neurons, but equal striatal DA denervation, in MPTP-treated aged xCT –/–  mice when compared to age-matched xCT +/+  littermates. To conclude, we reveal age-related protection against proteasome inhibition-induced nigrostriatal degeneration in xCT –/–  mice, while xCT deletion failed to protect nigral dopaminergic neurons of aged mice against MPTP-induced toxicity. Our findings thereby provide new insights into the role of system x  c   –  in mechanisms of dopaminergic cell loss and its interaction with aging.

frontiers in cellular neuroscience

Aged xCT-Deficient Mice Are Less Susceptible for Lactacystin-, but Not 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-, Induced Degeneration of the Nigrostriatal Pathway