Washington: A team led by scientists from The Scripps Research Institute (TSRI) has made a breakthrough discovery that could lead to new targets for Parkinson’s that may be useful in preventing the actual condition.
They have pinpointed a key factor controlling damage to brain cells in a mouse model of Parkinson’s disease.
The team, led by TSRI neuroscientist Bruno Conti, was looking for biological pathways that could connect the immune system’s inflammatory response to the damage seen in dopaminergic neurons. 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-13ra1 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.
Given that cells fared better without the receptor, the team next explored whether damage occurred when dopaminergic neurons that express IL-13Ra1 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 Cecilia Marcondes, a neuroimmunologist at TSRI and co-author of the study.
The finding also demonstrated that anti-inflammatory cytokines could contribute to neuronal loss.
The researchers noted they are not suggesting that inflammation is benign but that IL-13 and IL-4 may be harmful to neurons expressing the IL-13Ra1, 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.
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-13Ra1 is located on the X chromosome, where genetic variants are more likely to affect males.
And, though not definitive, other studies have suggested that Parkinson’s disease might be more common among allergy sufferers. Since IL-13 plays a role in controlling allergic inflammation, Conti wonders if the IL-13 receptor system might explain this correlation.
If further research confirms the IL-13 receptor acts in a similar way in human dopaminergic neurons as in mice, the discovery could pave the way to addressing the underlying cause of Parkinson’s disease.
Researchers might, for instance, find that drugs that block IL-13 receptors are useful in preventing loss of dopaminergic cells during neuroinflammation. And, since the IL-13 receptor forms a complex with the IL-4 receptor alpha, this might also be a target of interest. W
The team described their work in a paper published online by the Journal of Immunology.