Bettencourt, Conceição, Forabosco, Paola, Wiethoff, Sarah, Heidari, Moones, Johnstone, Daniel M., Botía, Juan A., Collingwood, Joanna F., Hardy, John, Milward, Elizabeth A., Ryten, Mina and Houlden, Henry (2016) Gene co-expression networks shed light into diseases of brain iron accumulation. Neurobiology of Disease, 87 . pp. 59-68. doi:10.1016/j.nbd.2015.12.004 ISSN 0969-9961.

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Abstract

Aberrant brain iron deposition is observed in both common and rare neurodegenerative disorders, including those categorized as Neurodegeneration with Brain Iron Accumulation (NBIA), which are characterized by focal iron accumulation in the basal ganglia. Two NBIA genes are directly involved in iron metabolism, but whether other NBIA-related genes also regulate iron homeostasis in the human brain, and whether aberrant iron deposition contributes to neurodegenerative processes remains largely unknown. This study aims to expand our understanding of these iron overload diseases and identify relationships between known NBIA genes and their main interacting partners by using a systems biology approach.

We used whole-transcriptome gene expression data from human brain samples originating from 101 neuropathologically normal individuals (10 brain regions) to generate weighted gene co-expression networks and cluster the 10 known NBIA genes in an unsupervised manner. We investigated NBIA-enriched networks for relevant cell types and pathways, and whether they are disrupted by iron loading in NBIA diseased tissue and in an in vivo mouse model.

We identified two basal ganglia gene co-expression modules significantly enriched for NBIA genes, which resemble neuronal and oligodendrocytic signatures. These NBIA gene networks are enriched for iron-related genes, and implicate synapse and lipid metabolism related pathways. Our data also indicates that these networks are disrupted by excessive brain iron loading.

We identified multiple cell types in the origin of NBIA disorders. We also found unforeseen links between NBIA networks and iron-related processes, and demonstrate convergent pathways connecting NBIAs and phenotypically overlapping diseases. Our results are of further relevance for these diseases by providing candidates for new causative genes and possible points for therapeutic intervention.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology R Medicine > RC Internal medicine
Divisions:	Faculty of Science, Engineering and Medicine > Engineering > Engineering
Library of Congress Subject Headings (LCSH):	Brain -- Diseases, Iron -- Metabolism -- Disorders
Journal or Publication Title:	Neurobiology of Disease
Publisher:	Academic Press
ISSN:	0969-9961
Official Date:	March 2016
Dates:	Date Event March 2016 Published 18 December 2015 Available 14 December 2015 Accepted 28 April 2015 Submitted
Volume:	87
Number of Pages:	10
Page Range:	pp. 59-68
DOI:	10.1016/j.nbd.2015.12.004
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	17 February 2016
Date of first compliant Open Access:	18 February 2016
Funder:	UK Brain Expression Consortium (UKBEC), Medical Research Council (Great Britain) (MRC), Engineering and Physical Sciences Research Council (EPSRC), National Health and Medical Research Council (Australia) (NHMRC) , Wellcome Trust (London, England), Brain Research Trust (BRT), National Institute for Health Research (Great Britain) (NIHR), University College London Hospitals Foundation NHS Trust‏ (UCLHFT), University College, London
Grant number:	G0901254 (MRC), G0802462 (MRC), EP/D066654/1 (EPSRC), 1078747 (NHMRC), MR/J004758/1 (MRC), WT093205MA (WT), WT104033/Z/14/Z (WT), WT089698 (WT)

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