Role of the IL-13 system in dopaminergic cell death

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Probing Parkinson’s disease Evidence suggests that interleukin 13 and its alpha 1 receptor may play an important role in the loss of dopaminergic neurons in a region of the brain called the substantia nigra pars compacta (SNc). Scientists aim to test this hypothesis, work which holds important implications for our understanding of the underlying causes of Parkinson’s Disease, as Professor Bruno Conti explains Parkinson’s disease (PD) is characterised

Dopaminergic neurons

by the loss of dopaminergic neurons in the SNc, yet the underlying causes of the condition are not fully understood. Based at the Scripps Research Institute, Professor Bruno Conti aims to develop a deeper understanding of the pathophysiology of the disease, building on earlier analysis of human health data. “My laboratory investigates how inflammatory processes can contribute to the neuronal loss occurring in PD. We focused our attention on a human chromosomal region linked to PD, which included the gene encoding for a protein known to regulate inflammation: the interleukin 13 receptor alpha 1 (IL13Rα1),” he says. This provided a basis for further investigation using mouse models. “When we checked if this receptor was present in the brain we found that it was expressed in the neurons of the SNc, the same that are lost in PD,” continues Professor Conti, “Next, we tested in mice whether lack of IL-13Rα1 rendered them more or less susceptible to experimentally induced PD. We found that the mice that did not have IL-13Rα1 were protected.”

This suggests that IL-13Rα1 is an important factor in the death of dopaminergic neurons in the SNc, a hypothesis that Professor Conti and his colleagues now plan to investigate more fully. There are several strands to this work, with the first centering on investigating how the activation of IL-13Rα1 can be detrimental. “There are two endogenous proteins that can activate IL-13Rα1: IL-13 and IL-4. While neither IL-13 nor IL-4 alone are toxic, they greatly potentiate the toxicity of special types of molecules known as reactive oxygen species and cause oxidative damage. Both these factors need to be considered in terms of understanding the underlying mechanisms behind the death of dopaminergic neurons,” says Professor Conti. “We are trying to figure out how this happens. If we find out which molecules mediate the potentiating effects that IL-13 and IL-4 have on oxidative stress, then each of those molecules could become drug targets for PD.” Another aim relates to understanding when IL-13 and IL-4 are produced. “We are studying which cells produce IL-13 in the brain, and under which circumstances,” outlines Professor Conti. Researchers have found that a type of glial cell called microglia, as well as some neurons, can make IL-13, now Professor Conti and his colleagues aim to probe deeper. “When do these cells decide to make IL-13? We know that allergies elevate the production of IL-13 and IL-4 in the periphery. Does this also occur in the brain? Is it possible that an allergy can be a risk factor for PD - if so, can limiting allergic reactions reduce the risk of developing PD? We are now investigating whether inducing allergies in the mouse, in quite a severe way, can lead to the production of IL-13 in the

IL-13 or IL-4 activate the IL-13Rα1 on dopaminergic neurons increasing the susceptibility of the cells to damage that can be caused by reactive oxygen species (ROS)

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central nervous system,” he says. “We are also investigating a model of chronic stress, as we know that stress increases the production of free radicals in the brain, and we want to check if it also leads to the production of IL-13. We’ve found that under some circumstances it does.” This research could help scientists build a deeper understanding of the underlying factors behind the development of PD, and in the long-term lead to improved treatment. The majority of current cases are considered idiopathic and sporadic, in that medical professionals are unclear why an individual has the disease, underlining the wider importance of this work. “Some genes have been demonstrated to cause PD in familial cases, but they account for only a small proportion of the overall total,” says Professor Conti. The molecules identified during the project could also hold potential as drug targets, something Professor Conti plans to investigate further in future. “Once we have identified the target we will team up with chemists to develop small molecules that will hopefully block this pathway, opening the way to the development of new drugs,” he outlines. Role of the IL-13 system in dopaminergic cell death We investigate the mechanisms by which inflammation can contribute to neurodegeneration. At present, we study how activation of the interleukin-13 receptor alpha 1 can cause the death of dopaminergic neurons. Our goal is to identify novel drug targets and to devise a strategy to prevent or treat Parkinson’s Disease. Funded by the National Institute of Health and by the Michael J. Fox Foundation. Professor Bruno Conti, Ph.D. Molecualr Medicine 10550 N. Torrey Pines Rd La Jolla, California 92037 mail SR 307 T: +858 784 9069 E: bconti@scripps.edu W: http://www.scripps.edu/conti/ Professor Bruno Conti, Ph.D. Born and raised in Italy he moved to the US in 1992. He trained in immunology at the New York Medical College and in molecular neuroscience at Cornell University. In 2000, he joined the Scripps Research Institute where he is a Professor in the department of Molecular Medicine.

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