Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/44516
Citations
Scopus Web of Science® Altmetric
?
?
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
1460-2083
Organisation: Centre for the Molecular Genetics of Development
Statement of
Responsibility: 
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; Animals; Zebrafish; Huntington Disease; Iron; Hemoglobins; Receptors, Transferrin; Zebrafish Proteins; RNA, Messenger; Gene Expression Regulation, Developmental; Genes, Dominant; Phenotype
Description: © The Author 2007. Published by Oxford University Press. All rights reserved.
Provenance: Human Molecular Genetics Advance Access published online on June 13, 2007
RMID: 0020073048
DOI: 10.1093/hmg/ddm138
Appears in Collections:Genetics publications
Centre for the Molecular Genetics of Development publications

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.