Abstract
Huntington's disease (HD) is a neurodegenerative disorder caused by a dominant CAG-repeat expansion in the huntingtin gene. Microglial activation is a key feature of HD pathology, and is present before clinical disease onset. The kynurenine pathway (KP) of tryptophan degradation is activated in HD, and is thought to contribute to disease progression. Indoleamine-2,3-dioxygenase (IDO) catalyzes the first step in this pathway; this and other pathway enzymes reside with microglia. While HD brain microglia accumulate iron, the role of iron in promoting microglial activation and KP activity is unclear. Here we utilized the neonatal iron supplementation model to investigate the relationship between iron, microglial activation and neurodegeneration in adult HD mice. We show in the N171-82Q mouse model of HD microglial morphologic changes consistent with immune activation. Neonatal iron supplementation in these mice promoted neurodegeneration and resulted in additional microglial activation in adults as determined by increased soma volume and decreased process length. We further demonstrate that iron activates IDO, both in brain lysates and purified recombinant protein (EC50 = 1.24 nM). Brain IDO activity is increased by HD. Neonatal iron supplementation further promoted IDO activity in cerebral cortex, altered KP metabolite profiles, and promoted HD neurodegeneration as measured by brain weights and striatal volumes. Our results demonstrate that dietary iron is an important activator of microglia and the KP pathway in this HD model, and that this occurs in part through a direct effect on IDO. The findings are relevant to understanding how iron promotes neurodegeneration in HD.
Highlights
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG-repeat expansion in exon 1 of the huntingtin gene (HTT) and results from expression of mutant huntingtin protein which misfolds in neurons and microglial cells [1,2]
Elevated indoleamine-2,3-dioxygenase activity in HD mouse brain is decreased by iron chelation
By using the neonatal iron supplementation (NIS) model of promotion in a genetic mouse HD model we demonstrate that iron challenge promotes morphologic and biochemical evidence of microglial activation which is linked to neurodegeneration
Summary
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG-repeat expansion in exon 1 of the huntingtin gene (HTT) and results from expression of mutant huntingtin protein (mHTT) which misfolds in neurons and microglial cells [1,2]. Iron activates microglia and indoleamine-2,3-dioxygenase activity in a mouse model of Huntington’s disease program, supported by the Institutional Development Award from NIH NIGMS 2P20GM103432, provided graduate and undergraduate fellowships to DWD and MR, respectively. The funding agencies had no input on study design, data analysis, or decision to publish
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