title: 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.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK. Electronic address: c.bettencourt@ucl.ac.uk.
authors.forename: Conceição
authors.initials: C
authors.lastname: Bettencourt
authors.affiliation: Istituto di Ricerca Genetica e Biomedica CNR, Cagliari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Forabosco
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wiethoff
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia; Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, The University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Moones
authors.initials: M
authors.lastname: Heidari
authors.affiliation: Bosch Institute and Discipline of Physiology, University of Sydney, NSW, Australia;
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Johnstone
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, UK.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Botía
authors.affiliation: School of Engineering, University of Warwick, Coventry, UK.
authors.forename: Joanna F
authors.initials: JF
authors.lastname: Collingwood
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia; Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, The University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Milward
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Department of Medical and Molecular Genetics, King's College London, London, UK.
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D007501:Iron / Q000378:metabolism; D019189:Iron Metabolism Disorders / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D019150:Neuroaxonal Dystrophies / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D066127:White Matter / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse; D007501:Iron
keywords: Human brain; Iron metabolism; NBIA; WGCNA; Whole-transcriptome analysis