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Type: Journal article
Title: Huntingtin-deficient zebrafish exhibit defects in iron utilization and development
Author: Lumsden, A.
Henshall, T.
Dayan, S.
Lardelli, M.
Richards, R.
Citation: Human Molecular Genetics, 2007; 16(16):1905-1920
Publisher: Oxford Univ Press
Issue Date: 2007
ISSN: 0964-6906
Organisation: Centre for the Molecular Genetics of Development
Statement of
Amanda L. Lumsden, Tanya L. Henshall, Sonia Dayan, Michael T. Lardelli and Robert I. Richards
Abstract: Huntington's disease is one of nine neurodegenerative disorders caused by expansion of CAG repeats encoding polyglutamine in their respective, otherwise apparently unrelated proteins. Despite these proteins having widespread and overlapping expression patterns in the brain, a specific and unique subset of neurons exhibits particular vulnerability in each disease. It has been hypothesized that perturbation of normal protein function contributes to the specificity of neuronal vulnerability, however the normal biological functions of many of these proteins including the HD gene product, Huntingtin (Htt), are unclear. To explore the roles of Htt, we have used antisense morpholino oligonucleotides to observe the effects of Htt deficiency in early zebrafish development. Knockdown of Htt expression resulted in a variety of developmental defects. Most notably, Htt-deficient zebrafish had hypochromic blood due to decreased haemoglobin production, despite the presence of iron within blood cells. Furthermore, transferrin receptor 1 transcripts were increased, suggesting cellular iron starvation. Provision of iron to the cytoplasm in a bio-available form restored haemoglobin production in Htt-deficient embryos. Since erythroid cells acquire iron via receptor-mediated endocytosis of transferrin, these results suggest a role for Htt in making endocytosed iron accessible for cellular utilization. Iron is required for oxidative energy production, and defects in iron homeostasis and energy metabolism are features of HD pathogenesis that are most pronounced in the major region of neurodegeneration. It is therefore plausible that perturbation of Htt's normal role in the iron pathway (by polyglutamine tract expansion) contributes to HD pathology, and particularly to its neuronal specificity.
Keywords: Embryo, Nonmammalian
Huntington Disease
Receptors, Transferrin
Zebrafish Proteins
RNA, Messenger
Gene Expression Regulation, Developmental
Genes, Dominant
Description: © The Author 2007. Published by Oxford University Press. All rights reserved.
Provenance: Human Molecular Genetics Advance Access published online on June 13, 2007
DOI: 10.1093/hmg/ddm138
Appears in Collections:Aurora harvest 6
Centre for the Molecular Genetics of Development publications
Genetics publications

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