Biology subjects

Donley, D.

Publications and source records attributed to Donley, D..

2 recordsLinked to original sources

bioRxiv2019

Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of Huntington's disease

Huntingtons 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.

neuroscience↗

bioRxiv2019

Mutant huntingtin protein alters the response of microglial cells to inflammatory stimuli

Huntingtons disease (HD) is a progressive neurodegenerative disease that affects the striatum and cerebral cortex. It is caused by a dominant CAG trinucleotide expansion in exon 1 of the HTT gene. Mutant huntingtin protein (mHtt) is expressed in neurons and immune cells. HD patients demonstrate altered blood cytokine profiles and altered responses of peripheral immune cells to inflammatory stimuli. However, the effects of mHtt on microglial immune responses are not fully understood. Herein we discuss the current understanding of how mHtt alters microglial inflammatory responses. Using lentivirus, we expressed the N171 N-terminal fragment of wild-type or mhtt containing 18 and 82 glutamine repeats in cultured EOC-20 microglial cells. We then measured responses to lipopolysaccharide or interleukin-6. Mutant huntingtin-expressing microglial cells produced less interleukin-6 and nitric oxide in response to lipopolysaccharide stimulation than wild-type huntingtin-expressing cells. However, mHtt-expressing microglia stimulated with interleukin-6 produced more nitric oxide than wild-type cells. Mutant huntingtin-expressing cells had higher basal NF-{kappa}B and further elevations of NF-{kappa}B after interleukin-6 but not lipopolysaccharide stimulation. Thus we demonstrate the potential of mHtt to dampen responses to lipopolysaccharide but potentiate responses to interleukin-6. This work adds to the emerging understanding that mHtt alters not only baseline status of cells but may also result in altered immune responses dependent on the nature of the inflammatory stimuli. We also present our perspective that in human HD the extent of inflammation may depend, in part, on altered responses to varied inflammatory stimuli including environmental factors such as infection.

neuroscience↗