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
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