Anti-inflammatory signals and neurodegeneration

Abstract Neuroimmune signals regulate neuronal function and survival. We have obtained multiple pieces of evidence indicating that activation of the heterodimeric interleukin-13 receptor alpha 1/interleukin-4 receptor alpha (IL- 13Rα1/IL-4Rα) affects the viability of midbrain dopaminergic (DA) neurons. We found that in the brain, IL- 13Rα1/IL-4Rα is preferentially expressed on the neurons of the substantia nigra pars compacta (SNc) that are lost in Parkinson’s disease (PD). We also showed that interleukin 13 (IL-13), produced during neuroinflammation by microglia and neurons, can modulate the activity of dopaminergic cells and increase their susceptibility to oxidative damage. Thus, having established that activation of IL-13Rα1 signaling can affect the survival of dopaminergic neurons during neuroinflammation, in the present application we wish to determine the molecular and cellular mechanisms by which this occurs. Specifically, we wish to test the hypothesis that IL-13 and neuronal IL-13Rα1 cause damage by stimulating a regulated cell death pathway called ferroptosis. We also wish to determine to what extent IL-13 and IL-13Rα1 contribute to neurodegeneration in a mouse model of alpha- synucleinopathy (α-Syn), a hallmark trait of PD that is associated with neuroinflammation and oxidative damage. This will help us determine whether targeting IL-13Rα1 signaling might be a viable approach to slow neurodegeneration in humans affected by an α-synucleinopathy such as PD. The ability of ruxolitinib, an FDA- approved drug that inhibits IL-13Rα1 signaling, and that of the novel ferroptosis inhibitor CMS121 to reduce IL- 13-mediated damage in vivo will also be tested. Finally, we propose in vivo experiments to test the hypothesis that a rare genetic variant of IL-13 found in individuals diagnosed with early-onset PD can contribute to more rapid loss of dopaminergic neurons in a mouse with the homologue of this mutation. If successful, these experiments will provide strong support for the hypothesis that IL-13 and IL-13Rα1 are novel targets for preventing PD or slowing its progression, at least in a sub-set of PD patients.