TY - JOUR T1 - Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of Huntington’s disease JF - bioRxiv DO - 10.1101/550905 SP - 550905 AU - David W. Donley AU - Marley Realing AU - Jason P. Gigley AU - Jonathan H. Fox Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/02/15/550905.abstract N2 - Huntington’s disease (HD) is a neurodegenerative disorder caused by a dominant CAG-repeat expansion in the huntingtin gene. Morphologic activation of microglia is a key marker of neuroinflammation that is present before clinical onset in HD patients. The kynurenine pathway of tryptophan degradation is restricted in part to microglia and is activated in HD, where it contributes to disease progression. Indoleamine-2,3-dioxygenase (IDO) is a microglial enzyme that catalyzes the first step in this pathway. HD brain microglial cells also accumulate iron; however, the role of iron in promoting microglial activation and the kynurenine pathway is unclear. Based on analyses of morphological characteristics of microglia, we showed that HD mice demonstrate an activated microglial morphology compared with controls. Neonatal iron supplementation resulted in additional microglial morphology changes compared with HD controls. Increased microglial activation in iron-supplemented HD mice was indicated by increased soma volume and decreased process length. In our assessment of whether iron can affect the kynurenine pathway, iron directly enhanced the activity of human recombinant IDO1 with an EC50 of 1.24 nM. We also detected elevated microglial cytoplasmic labile iron in N171-82Q HD mice, an increase that is consistent with the cellular location of IDO. We further demonstrated that neonatal iron supplementation, a model for studying the role of iron in neurodegeneration, activates IDO directly in the mouse brain and promotes neurodegeneration in HD mice. Kynurenine pathway metabolites were also modified in HD and by iron supplementation in wild-type mice. These findings indicate that iron dysregulation contributes to the activation of microglia and the kynurenine pathway in a mouse model of HD. ER -