Iron accumulates in Huntington's disease neurons: protection by deferoxamine

• Published in: PloS one 2013-10, Vol.8 (10), p.e77023-e77023
• Main Authors: Chen, Jianfang, Marks, Eileen, Lai, Barry, Zhang, Zhaojie, Duce, James A, Lam, Linh Q, Volitakis, Irene, Bush, Ashley I, Hersch, Steven, Fox, Jonathan H
• Format: Article
• Language: English
• Subjects: Accumulation; Animal models; Animals; BASIC BIOLOGICAL SCIENCES; Brain; Brain research; Corpus Striatum - metabolism; Corpus Striatum - pathology; Cytoplasm; Deferoxamine; Deferoxamine - administration & dosage; Deferoxamine - pharmacology; Diagnostic imaging; Disease Models, Animal; Female; Fluorescence; Homeostasis; Huntingtin; Huntington Disease - metabolism; Huntington Disease - physiopathology; Huntington Disease - prevention & control; Huntington's disease; Huntingtons disease; Immunoglobulins; Injections, Intraventricular; Iron; Iron - metabolism; Iron compounds; Iron Regulatory Protein 1 - metabolism; Iron Regulatory Protein 2 - metabolism; Male; Marks, Jonathan; Medical research; Membrane vesicles; Mental health; Mice; Mutation; Neostriatum; Nervous system diseases; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurons - metabolism; Neurosciences; NMR; Nuclear magnetic resonance; Oxidative stress; Pathogenesis; Perfusion; Phenotypes; Polyglutamine; Protein transport; Proteins; Receptors, Transferrin - metabolism; Rodents; Science & Technology - Other Topics; Staining; Structural analysis; Transferrin; Transferrin - metabolism; Transmission electron microscopes; Trinucleotide repeat diseases; Trinucleotide repeats; Ventricle; X ray fluorescence analysis; X-ray fluorescence; X-ray spectroscopy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0077023

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-encoding CAG expansion in the huntingtin gene. Iron accumulates in the brains of HD patients and mouse disease models. However, the cellular and subcellular sites of iron accumulation, as well as significance to disease progression are not well understood. We used independent approaches to investigate the location of brain iron accumulation. In R6/2 HD mouse brain, synchotron x-ray fluorescence analysis revealed iron accumulation as discrete puncta in the perinuclear cytoplasm of striatal neurons. Further, perfusion Turnbull's staining for ferrous iron (II) combined with transmission electron microscope ultra-structural analysis revealed increased staining in membrane bound peri-nuclear vesicles in R6/2 HD striatal neurons. Analysis of iron homeostatic proteins in R6/2 HD mice revealed decreased levels of the iron response proteins (IRPs 1 and 2) and accordingly decreased expression of iron uptake transferrin receptor (TfR) and increased levels of neuronal iron export protein ferroportin (FPN). Finally, we show that intra-ventricular delivery of the iron chelator deferoxamine results in an improvement of the motor phenotype in R6/2 HD mice. Our data supports accumulation of redox-active ferrous iron in the endocytic / lysosomal compartment in mouse HD neurons. Expression changes of IRPs, TfR and FPN are consistent with a compensatory response to an increased intra-neuronal labile iron pool leading to increased susceptibility to iron-associated oxidative stress. These findings, together with protection by deferoxamine, support a potentiating role of neuronal iron accumulation in HD.