Iron Accumulates in Huntington’s Disease Neurons: Protection by Deferoxamine
Abstract
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 perinuclear 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 andmore »
- Authors:
-
- Univ. of Wyoming, Laramie, WY (United States). Dept. of Veterinary Sciences and Neuroscience Graduate Program
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Univ. of Wyoming, Laramie, WY (United States). Dept. of Zoology and Physiology
- Mental Health Research Inst., Parkville, Melbourne, VIC (Australia); Univ. of Leeds, Leeds (United Kingdom). The Gaculty of Biologival Sciences. School of Molecular and Cellular Biology
- Mental Health Research Inst., Parkville, Melbourne, VIC (Australia)
- MassGeneral Inst. for Neurodegenerative Disease, Charlestown, MA (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences & Biosciences Division
- OSTI Identifier:
- 1627644
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Volume: 8; Journal Issue: 10; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Science & Technology - Other Topics
Citation Formats
Chen, Jianfang, Marks, Eileen, Lai, Barry, Zhang, Zhaojie, Duce, James A., Lam, Linh Q., Volitakis, Irene, Bush, Ashley I., Hersch, Steven, Fox, Jonathan H., and Skoulakis, Efthimios M. C. Iron Accumulates in Huntington’s Disease Neurons: Protection by Deferoxamine. United States: N. p., 2013.
Web. doi:10.1371/journal.pone.0077023.
Chen, Jianfang, Marks, Eileen, Lai, Barry, Zhang, Zhaojie, Duce, James A., Lam, Linh Q., Volitakis, Irene, Bush, Ashley I., Hersch, Steven, Fox, Jonathan H., & Skoulakis, Efthimios M. C. Iron Accumulates in Huntington’s Disease Neurons: Protection by Deferoxamine. United States. https://doi.org/10.1371/journal.pone.0077023
Chen, Jianfang, Marks, Eileen, Lai, Barry, Zhang, Zhaojie, Duce, James A., Lam, Linh Q., Volitakis, Irene, Bush, Ashley I., Hersch, Steven, Fox, Jonathan H., and Skoulakis, Efthimios M. C. Fri .
"Iron Accumulates in Huntington’s Disease Neurons: Protection by Deferoxamine". United States. https://doi.org/10.1371/journal.pone.0077023. https://www.osti.gov/servlets/purl/1627644.
@article{osti_1627644,
title = {Iron Accumulates in Huntington’s Disease Neurons: Protection by Deferoxamine},
author = {Chen, Jianfang and Marks, Eileen and Lai, Barry and Zhang, Zhaojie and Duce, James A. and Lam, Linh Q. and Volitakis, Irene and Bush, Ashley I. and Hersch, Steven and Fox, Jonathan H. and Skoulakis, Efthimios M. C.},
abstractNote = {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 perinuclear 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.},
doi = {10.1371/journal.pone.0077023},
journal = {PLoS ONE},
number = 10,
volume = 8,
place = {United States},
year = {Fri Oct 11 00:00:00 EDT 2013},
month = {Fri Oct 11 00:00:00 EDT 2013}
}
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