Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of Huntington’s disease
Autor: | David W. Donley, Jonathan H. Fox, Marley Realing, Jason P. Gigley |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Kynurenine pathway Biochemistry law.invention Mice Medical Conditions Aromatic Amino Acids Spectrum Analysis Techniques 0302 clinical medicine Animal Cells law Medicine and Health Sciences Amino Acids Indoleamine 2 3-dioxygenase Immune Response Kynurenine Protein Metabolism chemistry.chemical_classification Huntingtin Protein 0303 health sciences Multidisciplinary Microglia Organic Compounds Chemistry Neurodegeneration Tryptophan Brain Neurodegenerative Diseases Animal Models Flow Cytometry Cell biology Huntington Disease medicine.anatomical_structure Experimental Organism Systems Neurology Genetic Diseases Spectrophotometry Cerebral cortex Physical Sciences Recombinant DNA Medicine Cytophotometry Cellular Types Anatomy medicine.symptom Research Article Science Iron Immunology Mice Transgenic Mouse Models Glial Cells Inflammation Research and Analysis Methods Gene Expression Regulation Enzymologic 03 medical and health sciences Model Organisms Signs and Symptoms Huntington's disease medicine Animals Indoleamine-Pyrrole 2 3 -Dioxygenase Microglial Cells Neuroinflammation 030304 developmental biology Clinical Genetics Activator (genetics) Autosomal Dominant Diseases Organic Chemistry Chemical Compounds Biology and Life Sciences Proteins Cell Biology medicine.disease Neostriatum Disease Models Animal Metabolism 030104 developmental biology Enzyme Animal Studies Clinical Medicine 030217 neurology & neurosurgery |
Zdroj: | PLoS ONE PLoS ONE, Vol 16, Iss 5, p e0250606 (2021) |
Popis: | 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. |
Databáze: | OpenAIRE |
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