Deciphering the pathways that protect from IL-13-mediated potentiation of oxidative stress-induced dopaminergic nerve cell death.

The majority of Parkinson's disease (PD) cases are sporadic with only about 10% of PD patients having a family history of the disease suggesting that this neurodegenerative disorder is the result of both environmental and genetic factors. Both oxidative stress and neuroinflammation are thought to contribute to PD. Previously, we showed that the activation of interleukin 13 receptor alpha 1 (IL-13Rα1) increases the sensitivity of dopaminergic neurons to oxidative damage both in cultured cells and in animals. In this study, we investigated the pathways involved in the IL-13-mediated potentiation of oxidative stress-induced dopaminergic cell death using a combination of cell survival assays and Western blotting with appropriate antibodies. In addition, siRNA was used to examine the role of 4E-BP1 in this cell toxicity paradigm. We show that activation of both the Jak-Stat and PI3 kinase-mTOR pathways play key roles in the promotion of cell death by IL-13 in the presence of mild oxidative stress. The Jak 1/2 inhibitor ruxolitinib, the mTOR inhibitor rapamycin and the PI3 kinase inhibitor LY294002 all prevented the potentiation of cell death by IL-13. Moreover, 4E-BP1, a target of mTOR, appeared to mediate the protective effects of rapamycin. Together, these results indicate that multiple signaling pathways downstream of IL-13Rα1 activation play a role in the toxic effects of IL-13 in dopaminergic neurons in the presence of mild oxidative stress and suggest that any of these pathways might provide potential targets for the treatment of PD.