The IL-13 receptor system plays a key role in controlling damage to brain cells in a mouse model of Parkinson's disease—a discovery that researchers hope will yield new targets capable of preventing the disorder.
In results published in the Journal of Immunology, the research team led by neuroscientist Bruno Conti, Ph.D., and other investigators at The Scripps Research Institute (TSRI) used a mouse model in which chronic peripheral inflammation causes both neuroinflammation and loss of dopaminergic neurons similar to that seen in Parkinson's. The team looked at mice having or lacking a protein known as interleukin-13 receptor alpha 1 chain (IL-13Ra1), located in the PARK12 locus linked to Parkinson's, and then compared the number of dopaminergic neurons in the brain region of interest.
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.
Researchers discovered, to their surprise, that in the mouse brain, IL-13Ra1 is found only on the surface of dopaminergic neurons. That led the team to set up long-term experiments using a mouse model in which chronic peripheral inflammation caused both neuroinflammation and loss of dopaminergic neurons similar to that seen in Parkinson's disease. The team examined mice having or lacking IL-13Ra1, then compared their number of dopaminergic neurons in the substantia nigra pars compacta, a region of the brain regulating movements and coordination.
The researchers expected that the absence of an IL-13 receptor would increase inflammation and cause neuronal loss to get even worse. Instead, neurons got better. The team next explored whether damage occurred when dopaminergic neurons that express IL-13Rα1 were exposed to IL-13 or IL-4. Exposure to either cytokine 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 TSRI neuroimmunologist who was first author of the study along with Brad Morrison, then a TSRI postdoctoral fellow and now at University of California, San Diego.
Researchers say additional clues point to the IL-13 receptor system playing a major role in Parkinson's, such as the finding in some other studies that Parkinson's is more common in males and allergy sufferers. IL-13 is known to help control allergic inflammation, while the IL-13Rα1 gene is located on the X chromosome, where genetic variants are more likely to affect males.