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Gene co-expression networks shed light into diseases of brain iron accumulation.

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.

journal_name

Neurobiol Dis

journal_title

Neurobiology of disease

authors

Bettencourt C,Forabosco P,Wiethoff S,Heidari M,Johnstone DM,Botía JA,Collingwood JF,Hardy J,UK Brain Expression Consortium (UKBEC).,Milward EA,Ryten M,Houlden H

doi

10.1016/j.nbd.2015.12.004

subject

Has Abstract

pub_date

2016-03-01 00:00:00

pages

59-68

eissn

0969-9961

issn

1095-953X

pii

S0969-9961(15)30106-6

journal_volume

pub_type

杂志文章

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Gene co-expression networks shed light into diseases of brain iron accumulation.