Iron Accumulates in Huntington’s Disease Neurons: Protection by Deferoxamine

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.

doi:10.1371/journal.pone.0077023

Iron Accumulates in Huntington’s Disease Neurons: Protection by Deferoxamine

Journal Article · Fri Oct 11 04:00:00 EDT 2013 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0077023· OSTI ID:1627644

Chen, Jianfang ^[1]; Marks, Eileen ^[2]; Lai, Barry ^[3]; Zhang, Zhaojie ^[4]; Duce, James A. ^[5]; Lam, Linh Q. ^[6]; Volitakis, Irene ^[6]; Bush, Ashley I. ^[6]; Hersch, Steven ^[7]; Fox, Jonathan H. ^[2]; Skoulakis, Efthimios M. C.

Univ. of Wyoming, Laramie, WY (United States). Dept. of Veterinary Sciences and Neuroscience Graduate Program; DOE/OSTI
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)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences & Biosciences Division

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1627644

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 10 Vol. 8; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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