...After searching human genomics databases, the team's attention was caught by a gene encoding a protein known as interleukin-13 receptor alpha 1 chain (IL-13Ra1), as it is located in the PARK12 locus, which has been linked to Parkinson's. IL-13rα1 is a receptor chain mediating the action of interleukin 13 (IL-13) and interleukin 4 (IL-4), two cytokines investigated for their role as mediators of allergic reactions and for their anti-inflammatory action. With further study, the researchers made the startling discovery that in the mouse brain, IL-13Ra1 is found only on the surface of dopaminergic neurons. "...

...The scientists set up long-term experiments using a mouse model in which chronic peripheral inflammation causes both neuroinflammation and loss of dopaminergic neurons similar to that seen in Parkinson's disease. The team looked at mice having or lacking IL-13Ra1 and then compared the number of dopaminergic neurons in the brain region of interest.

The researchers expected that knocking out the IL-13 receptor would increase inflammation and cause neuronal loss to get even worse. Instead, neurons got better. "We were very surprised at first," said Conti. "When we stopped to think, we got very excited because we understood that there was something new going on." Given that cells fared better without the receptor, the team next explored whether damage occurred when dopaminergic neurons that express IL-13Rα1 were exposed to IL-13 or IL-4. But exposure to IL-13 or IL-4 alone did not induce damage. However, when the scientists exposed the neurons to oxidative compounds, they found that both IL-13 and IL-4 greatly enhanced the cytotoxic effects of oxidative stress.

"This finally helps us understand a basic mechanism of the increased susceptibility and preferential loss of dopaminergic neurons to oxidative stress associated with neuroinflammation," said Marcondes.

The finding also demonstrated that anti-inflammatory cytokines could contribute to neuronal loss. In their article, the authors note they are not suggesting that inflammation is benign but that IL-13 and IL-4 may be harmful to neurons expressing the IL-13Rα1, despite their ability to ultimately reduce inflammation. "One could say that it is not the fall that hurts you, but how you stop," said Conti. More Clues Along with these results, additional clues suggest that the IL-13 receptor system could be a major player in Parkinson's. For instance, some studies show Parkinson's as more prevalent in males, and the gene for IL-13Rα1 is located on the X chromosome, where genetic variants are more likely to affect males...

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